Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 40.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (17.0 g) and N-(4-bromobutyl)phthalimide (15.8 g) were reacted and treated in the same manner as in Preparation Example 150 to give 9.3 g of 4-amino-5-chloro-N-(1-(4-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)butyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][C:33](Br)=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[N:29]=[CH:28][C:27]([C:30]5[CH:31]=[N:32][C:33]([C:16]6[CH:17]=[CH:18][C:19]7[N:7]([C:1]8[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=8)[C:8]8[C:13]([C:14]=7[CH:15]=6)=[CH:12][CH:11]=[CH:10][CH:9]=8)=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(-c2ccc(Br)nc2)cn1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
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: O
Solvent: C1CCOC1
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc(-c5ccc(-c6ccc7c(c6)c6ccccc6n7-c6ccccc6)nc5)cn4)ccc32)cc1
Temperature: 85 °C
Yield: 64.2 %

Procedure:
A mixture of (9-phenyl-9H-carbazol-3-yl)boronic acid (1.41 g, 4.92 mmol), 6,6′-dibromo-3,3′-bipyridine (0.750 g, 2.39 mmol), tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.143 mmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) was degassed with argon for about 25 min while stirring. The reaction mixture was then maintained at about 85° C. under argon. Upon confirming consumption of the starting material by thin layer chromatography (TLC) (SiO2, dichloromethane), the reaction was cooled to RT and poured over CH2Cl2 (ca. 350 mL). The organics were then washed with saturated NaHCO3, H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude via flash chromatography (SiO2, 100% CH2Cl2 to 29:1 CH2Cl2-acetone) afforded Compound 22 (0.98 g, 64%) as an off-white solid. MS (ES+) m/z: 639 (C46H30N4 requires 639).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl.C(N(CC)CC)C>[Si:15]([O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1cccc(C=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymethylbenzaldehyde (step 1) (3 g) in methylene chloride (15 mL) and triethylamine (4.1 mL) was slowly added t-butylchlorodiphenylsilane (8 mL). Finally, a few mgs of 4-pyrrolidinopyridine was added as a catalyst. The reaction mixture was stirred overnight at room temperature The solution was quenched with 25% ammonium acetate and extracted with ethyl acetate, which was washed with brine (2x), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography, using 4% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][C:24]([F:23])([F:34])[F:35])=[CH:27][CH:28]=5)[CH2:20][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To (8S,9aS)-8-[(5-cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (50 mg, 0.154 mmol, Part D) in anhydrous dichloroethane (0.7 mL) was added 4-(trifluoromethoxy)benzaldehyde (38 mg, 0.2 mmol), and N-ethyl-N-isopropylpropan-2-amine (39.8 mg, 0.308 mmol). After 10 minutes, sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 33 mg (46.4% yield) of the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (m, 2H), 0.98 (m, 2H), 1.82 (m, 1H), 2.12 (m, 1H), 2.20-2.32 (m, 2H), 2.42 (dd, J=12, 8 Hz, 1H), 2.61 (m, 1H), 2.70-2.90 (m, 3H), 3.50 (br d, J=12 Hz, 1H), 3.57 (br d, J=12 Hz, 1H), 3.62-3.72 (m, 2H), 4.12 (m, 1H), 5.29 (m, 1H), 7.31 (d, J=9 Hz, 2H), 7.43 (d, J=9 Hz, 2H), 8.15 (s, 1H), 8.18 (s, 1H); MS (ESI) m/z 463.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:21][CH3:22])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:7]([NH2:20])[N:6]=1.C1C(=O)N([Br:30])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:30][C:10]1[N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:20])[N:6]=[C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:21][CH3:22])[N:13]=2
Reactant: CCC(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
A solution of 2-[(2-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (245 mg) in dry chloroform (2.9 mL) was cooled to 0° C. and NBS (150 mg) was added to give a green/brown solution. The reaction mixture was stirred at room temperature for 6 h. The mixture was taken up into DCM (20 mL) and was washed with water (20 mL). The organics were separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as green solid (292 mg).
Reaction SMILES: C1(OC2C=CC=CC=2[N+:14]([O-:16])=[O:15])C=CC=CC=1.O(C1C=CC=CC=1N)C1C=CC=CC=1.[O:31]([C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[NH:40][C:41](=[O:43])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N+]([O-])(O)=O>C(O)(=O)C>[N+:14]([C:46]1[CH:45]=[CH:44][C:39]([NH:40][C:41](=[O:43])[CH3:42])=[C:38]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:47]=1)([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1
Agent: Nc1ccccc1Oc1ccccc1
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1Oc1ccccc1
Yield: 60 %

Procedure:
o-Nitrophenyl phenyl ether was reduced catalytically to o-phenoxyaniline, m. 43°-5°, which was acetylated to 2'-phenoxyacetanilide, m. 82°-4°. Yields from both reactions were essentially quantitative. The 2'-phenoxy-acetanilide was dissolved in acetic acid and treated at 60°-80° with red fuming nitric acid to produce a 60-70% yield of 4'-nitro-2'-phenoxy-acetanilide, m. 176°-183°. This was deacetylated by refluxing with methanolic hydrochloric acid to 4-nitro-2-phenoxyaniline, m. 116°-8°. The yield was 99% of theoretical.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([CH3:30])([C:23]([O:25]C(C)(C)C)=[O:24])[C:16]([O:18]C(C)(C)C)=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([CH3:30])([C:23]([OH:25])=[O:24])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(C)(C(=O)O)C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Di-tert-butyl [2-(ethoxycarbonyl)-1-benzothien-6-yl](methyl)malonate (0.26 g, 0.598 mmol) was dissolved in DCM (1.5 mL) and TFA (1.5 mL) was added. The solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.193 g of product (pale yellow solid, 100%). 1H NMR (DMSO-d6) δ 13.12 (br s, 2H), 8.14 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.77 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:12]([CH:13]([C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)[C@H](C[N+](=O)[O-])c1ccccc1
Reaction time: 24 h

Procedure:
To a solution (0.40 ml) of trans-β-nitrostyrene (29.8 mg, 0.20 mmol) and diethyl malonate (0.061 ml, 0.40 mmol) in toluene was added, as an asymmetric catalyst, (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (8.2 mg, 0.02 mmol) obtained in Example 1A at room temperature under an argon atmosphere. After 24 hr, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (elution solvent: n-hexane/diethyl ether) to give the title compound as colorless needle crystals (53.3 mg, yield 86%). The yield and optical purity are shown in Tables 1-3. melting point: 45-47° C. (n-hexane/diethyl ether)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>C(O)(=O)C.[Pd].C>[NH2:1][C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C

Procedure:
12.92 g (40mmols) of Z-Thr(tBu)-OMe are hydrogenated in 200 ml of glacial acetic acid and 3 g of Pd-charcoal (10%) at room temperature. The hydrogen uptake is finished after 1 hour. The solution is freed of the catalyst by filtration and is evaporated in a waterpump vacuum at 35°C. After drying in a high vacuum at 35°C 7.3 g of an oil result, which according to a thin layer chromatogram is a single substance and is directly further used.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:10]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:26][C:25]1[CH:27]=[CH:28][C:22]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCc1ccc(N=C(C)c2ccccc2)cc1
Yield: 93.7 %

Procedure:
solution of acetophenone (33.5 g), p-dodecyl aniline (73 g), benzene (50 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(α-methyl benzylidene)-p-dodecyl aniline (V) (95 g). V had a melting point of 47° C.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-]1C=CC=C1.[Fe+2:11].[Al+3].[Cl-].[Cl-].[Cl-].[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.[CH:1]1([Fe+:11])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: c1cc[cH-]c1
Reactant: [Fe+2]
Agent: [Zr+4]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cc(C)cc(C)c1
Product: [Fe+]C1C=CC=C1

Procedure:
In accordance with the procedure of Example 4, 10 g (0.043 mol) of ZrCl4 are added at 60° C. under argon over the course of 1 hour and 10 minutes to a stirred mixture of 60 ml of mesitylene, 8 g (0.043 mol) of ferrocene and 5.7 g (0.043 mol) of sublimed AlCl3. Working up is effected as in Example 4, affording 20.1 g (83.4% of theory) of crude (η6 -mesitylene)-η5 -(cyclopentadienyl)-iron(II) tetrapnenylborate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[N:40]=[C:36]([C:32]2[CH:31]=[C:30]([C:29]3[CH2:28][C:27](=[O:50])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[S:37][CH:38]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.31 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.09 g).
Reaction SMILES: CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[I-:25].[Na+].Cl>CN(C)C=O.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([I:25])[CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(F)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
Chloramine-T trihydrate (50 g, 178 mmol) was added to a stirred, cooled (0° C.) solution of 4-fluorophenol (20 g, 178 mmol) and sodium iodide (26.7 g, 178 mmol) in dimethylformamide (250 mL). The mixture was stirred at 0° C. for 1 h., and poured into water (1000 mL). The mixture was acidified with hydrochloric acid (1M) and extracted with ether (4×200 mL). The combined organic fractions were washed with aqueous sodium thiosulfate (5%, 3×100 mL), water (2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The reside was purified by flash column chromatography on silica gel, eluting with hexane/CH2Cl2 to give the title compound as an off-white solid (7.8 g, 18%). 1H NMR (360 MHz, CDCl3) δ 5.08 (1H, s), 6.90-7.01 (2H, m), and 7.37 (1H, dd, J 7.6, 2.9 Hz).
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:22])C>>[CH3:13][C:2]1([CH3:14])[C:3](=[O:22])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:6]1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccncc1
Solvent: CCNCC
Product: CC1(C)OC(c2ccncc2)=CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (1.8 g, 9.50 mmol) in ethanol (18 mL) was added diethyl amine (1.04 g, 14.0 mmol) in EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.3 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:34]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-3-(3-bromophenyl)acrylic acid (100 g, 0.44 mol) and triethylamine (0.48 mol) in toluene (1000 mL) was added diphenylphosphoryl azide (127.4 g, 0.45 mol) dropwise at 0-10° C. The mixture was stirred at room temperature overnight. Thin layer chromatography (petroleum ether/ethyl acetate=8:1) indicated completion of reaction. The resulting mixture was washed with 1 N sodium hydroxide (500 mL) and extracted with ethyl acetate (2000 mL×3). The organic layer was concentrated to give crude (E)-1-azido-3-(3-bromophenyl)prop-2-en-1-one, which was used in the next step directly.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.C([CH2:38][C:39]([NH2:44])([CH3:43])[C:40](O)=[O:41])(OC(C)(C)C)=O>>[NH2:44][C:39]([CH3:43])([CH3:38])[C:40]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:22]2[S:23][C:9]3[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[N:13][C:12]([C:14]4[CH:19]=[N:18][C:17]([NH2:20])=[N:16][CH:15]=4)=[N:11][C:10]=3[CH:21]=2)[CH2:30][CH2:29]1)=[O:41]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Reactant: CC(C)(C)OC(=O)CC(C)(N)C(=O)O
Agent: Cl
Product: CC(C)(N)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with Boc-2-aminoisobutyric Acid via General Procedure B followed by Boc removal with TFA to generate 28.8 mg of 103 after purification. MS (Q1) 498.3 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].CO>C(OCC)(=O)C>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(C(=O)/C=C/N(C)C)ccc1OC
Temperature: 95 °C
Yield: 90.1 %

Procedure:
Methyl 5-acetyl-2-methoxybenzoate (11.98 g, 48.0 mmol) was added to N,N-dimethylformamide dimethyl acetal (44.6 g, 374.5 mmol) held under a nitrogen atmosphere. The resulting solution was heated at 95° C. for 60 minutes. Methanol (10 ml) was then removed by atmospheric distillation and further N,N-dimethylformamide dimethyl acetal (8.90 g, 74.9 mmol) added. The resulting solution was heated at 95° C. for a further 270 minutes. The reaction was then cooled to 50° C. and ethyl acetate (35 mL) added. Solvent (35 mL) is removed from the reaction by atmospheric distillation and fresh ethyl acetate (35 mL) added. Further solvent (35 mL) is removed from the reaction by atmospheric distillation and fresh ethyl acetate (50 mL) added. The reaction mixture is cooled to RT whereby the desired product crystallises out as a granular, free flowing solid. The solid was isolated by filtration, washed twice with fresh ethyl acetate (2×30 mL) and dried to constant weight to afford 11.39 g of the desired methyl 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzoate (8).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40]>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: CN(C)CCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Agent: Cl
Product: CN(C)CCN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=577.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 1-chloro-2-dimethylaminoethane hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N12CCN(CC1)CC2.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([NH:1][CH2:2][CH2:3][C:4]2([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH2:14][CH2:13]3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(=O)(=O)c4ccc(C)cc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (228 mg) in dichloromethane (3 mL) were added 1,4-diazabicyclo[2.2.2]octane (108 mg) and p-toluenesulfonyl chloride (120 mg) successively. The solution was stirred at room temperature for 6 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3 to 1:2)] to give the title compound (265 mg).
Reaction SMILES: Cl.[OH:2][NH3+:3].[C:4]([O:13]CC)(=O)[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7]>[OH-].[Na+].O1CCOCC1>[C:4]([NH:3][OH:2])(=[O:13])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7]
Reactant: [NH3+]O
Reactant: CCOC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NO)c1ccccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
Hydroxylammonium hydrochloride (15 g) was dissolved in 10% aqueous sodium hydroxide solution (220 mL), and a solution of ethyl salicylate (24 g) in 1,4-dioxane (70 mL) was gradually added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated until the amount thereof became almost the half, and acidified with conc. hydrochloric acid. The precipitated solid was collected by filtration, which was then recrystallized from methanol to give salicylhydroxamic acid (12 g) as white crystals.