Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:32])=[C:17]([O:20][CH:21]4[CH2:24][N:23](C(OCCCC)=O)[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:23]1[CH2:24][CH:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[OH:32])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[C:3]=2[F:33])[CH2:22]1
Reactant: CCCCOC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
100 mg of the compound obtained in step 1) was diluted with 2 ml of methylene chloride, and 0.2 ml of trifluoroacetic acid was added thereto. The resulting mixture was stirred at room temperature for one hour. After the reaction terminated, the resulting solution was distilled under a reduced pressure to remove a solvent. The resulting residue was alkalinized with a saturated sodium bicarbonate and extracted with a mixed solvent of chloroform and 2-propanol (3:1). The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (methylene chloride:methanol=10:1) to obtain the title compound (69 mg, 87%).
Reaction SMILES: [F:1][C:2]1([CH2:16][OH:17])[CH2:7][CH2:6][C:5]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:24]=[N:25][C:26]=1Cl.[NH4+].[Cl-]>CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:24]=[N:25][C:26]=1[O:17][CH2:16][C:2]1([F:1])[CH2:3][CH2:4][C:5]2([O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11]2)[CH2:6][CH2:7]1
Reactant: OCC1(F)CCC2(CC1)Oc1ccccc1O2
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(OCC2(F)CCC3(CC2)Oc2ccccc2O3)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 350C (89 mg) in N,N-dimethylformamide (3 mL) was added NaH (65% in mineral oil, 36 mg). The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (85 mg) was added. The mixture was stirred overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[C:19]3[CH:40]=[CH:39][CH:38]=[CH:37][C:20]=3[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=O)=[CH:12][CH:11]=1.[BH4-].[Li+].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1COCC1.CO.[Cl-].[Na+].O.ClCCl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:18]2[C:19]3[CH:40]=[CH:39][CH:38]=[CH:37][C:20]=3[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[CH:12][CH:11]=1
Reactant: O=C(c1ccc(OCCN2CCCC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCN1CCOc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.1 %

Procedure:
2-[4-[2-(1-Pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl ketone (120 mg) was dissolved in THF/MeOH (3.0/0.3 mL) and treated with lithium borohydride (40 mg) in one portion and allowed to stir at ambient temperature for 4 h. The reaction mixture was diluted with brine (30 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give the crude alcohol. This material was dissolved in dichloromethane (3.0 mL), treated with triethylsilane (0.25 mL) and trifluroacetic acid (0.2 mL) sequentially, allowed to stir at ambient temperature for 2 h, and concentrated under reduced pressure. The residue was extracted with -dichloromethane (20 mL×3) from saturated aqueous sodium bicarbonate (30 mL). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound (27 mg).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][C@@:16]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@@H:20]1[CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=3[C@H:19]1[CH2:18][CH2:17]2.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C1COCC1>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][C@H:24]2[CH2:23][CH2:22][C@H:21]3[C@H:20]4[C@H:19]([CH2:18][CH2:17][C@:16]23[CH3:15])[C:29]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26]4)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NC(c3ccccc3)c3ccccc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A solution of aminodiphenylmethane (5.50 g) in methanol (100 ml) was stirred at room temperature. Added sequentially to this solution were glacial acetic acid (1.8 ml, 1.8 g), estrone methyl ether (8.52 g), sodium cyanoborohydride (2.3 g), and THF (80 ml). The mixture was stirred at room temperature for 8 days. Additional NaB(CN)H3 (1.5 g), amine (5.5 g), and acetic acid (1.8 g) were added after four days of the reaction time. Excess solvent was removed under reduced pressure and water (300 ml) was added to the solid residue. The mixture was made alkaline with 50% aqueous NAOH and was extracted with ether (3×). The extracts were dried (MgSO4), filtered, and concentrated, giving an oily residue. This crude product was chromatographed (500 g silica gel, 5% ethyl acetate-hexane, 350 ml fractions) on a gravity column. The desired product was eluted in fractions 4-7, and after recrystallization from methanol gave a first crop of crystals, mp 127° -129° C., and a second crop. A sample was recrystallized again from methanol and gave an analytical sample of the title compound, mp 127°-129° C. (PLA2, diabetes)
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O1CCCCC1.[O:41]1[CH:46]=[CH:45][C:44]([C:47](O)=[O:48])=[CH:43][CH2:42]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(=O)([O-])O.[Na+]>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][N:32]([C:47]([CH:44]2[CH2:45][CH2:46][O:41][CH2:42][CH2:43]2)=[O:48])[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Reactant: O=C(O)C1=CCOC=C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOCC1
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(C(=O)C3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (453 mg), tetrahydropyran-2H-pyran-4-carboxylic acid (150 mg) and 1-hydroxy-1H-benzotriazole (84 mg) in acetonitrile (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)] to give the title compound as a colorless amorphous compound (518 mg, 92%).
Reaction SMILES: S([O:5][C:6]1[C:7]([O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]=1[O-:12])=[O:8])([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O>[O:8]=[C:7]1[O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]([OH:12])=[C:6]1[OH:5]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1OS(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Pyridinium L-ascorbate 2-sulfate is a dimorphic crystalline solid with m.p. 119°-120.5° or 133°-4°, [α]D25 + 40° (c 1.0, water). The nuclear magnetic resonance spectrum of the compound gave the correct proportion of aromatic to ascorbic acid protons for the monopyridinium salt.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([O:17]C)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].OC1C(C)=C2C(=C(C)C=1C)OC(OC)CC2>C(O)(=O)C.O>[C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([OH:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: COC1CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(O)O2

Procedure:
A solution of (±)-6-acetoxy-2-methoxy-5,7,8-trimethylchroman, prepared as described in Example 2 from 0.1 mole of (±)-6-hydroxy-2-methoxy-5,7,8-trimethylchroman, in 200 ml. of 1:1 acetic acid-H2O was heated at reflux under a nitrogen atmosphere for 1.5 hours. The mixture was cooled, diluted with 200 ml. of H2O and filtered. The solid was washed with H2O and dried to give (±)-6-acetoxy-2-hydroxy-5,7,8-trimethylchroman as a white solid, m.p. 115°-120°.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:22]([OH:35])[C@H:21]([CH3:36])[O:20][C:19]2=[O:37])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2].[CH:38]1[CH:43]=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:39]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:22]([O:35][CH2:43][CH:38]=[CH2:39])[C@H:21]([CH3:36])[O:20][C:19]2=[O:37])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1OCOC(C)=O
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=CCO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)COC(=O)[C@@H]1Cc1ccccc1
Yield: 68 %

Procedure:
Compound 8 was prepared in 68% yield using Compound 3 (150 mg, 0.29 mmol) with dppb (12 mg, 0.03 mmol), Pd2dba3 (5.30 mg, 0.006 mmol) and ethyl methallylcarbonate (41 mg, 0.31 mmol). Purification by flash column chromatography on silica gel eluting with a mixture of hexane-acetone (1:1) gave a white foam: MS: (M+1)+=557, (M−1)+=555. Spectral data were consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[CH2:7][CH2:6][CH:5]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc3oc(=O)[nH]c3c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4oc(=O)[nH]c4c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 5-(1-hydroxy-4-oxo-cyclohexyl)-3H-benzooxazol-2-one (as prepared in Example 5, Step A) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:6]=1.O.O.Cl[Sn]Cl.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc(N)cc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10152.9 %

Procedure:
4-(4-methyl-1H-imidazol-1-yl)nitrobenzene (22.5 g; 0.87 mmol) is dissolved in abs. ethanol (250 mL), then SnCl2.2H2O (125 g; 0.55 mol) is added portion-wise, on cooling at 0° C. The resulting mixture is stirred at r.t. for 2 hours and heated at reflux overnight. The reaction mixture is then cooled at r.t. and the pH is adjusted to 12, by adding 30% KOH (500 mL), then KOH pellets under stirring. The resulting suspension is filtered and the cake is washed with ethanol, the combined filtrate and washings are concentrated and the residue is extracted with DCM. Concentration of the combined organic extracts afforded the title product as a slight brown solid (15.3 g; 80%), m.p.: 122-125° C. C10H11N3, MW 173.22.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[F:18][C:19]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:20]=1[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:18][C:19]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:20]=1[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc(Oc2c(F)c(F)c(F)c(F)c2F)c1
Product: Fc1c(F)c(F)c(Oc2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)c(F)c1F

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-(2,3,4,5,6-pentafluorophenoxy)aniline (106 mg, 0.386 mmol) similar to Example 58 and isolated as a yellow solid (65 mg, 68%). 1H NMR (DMSO-d6): 10.46 (s, 1H), 9.24 (s, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.56–8.52 (m, 1H), 7.77 (s, 1H), 7.59–7.55 (m, 1H), 7.50–7.41 (m, 2H), 7.14 (s, 1H), 6.94–6.92 (m, 1H).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:5]=[CH:4][CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: Ic1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc5ccccc45)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodonaphthalene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 502.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:32]=[CH:33][C:34]([CH3:38])=[C:35]([OH:37])[CH:36]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH2:47][O:48][CH3:49]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:32]=[CH:33][C:34]([CH3:38])=[C:35]([O:37][CH2:46][CH2:47][O:48][CH3:49])[CH:36]=5)=[N:23][N:22]=4)=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(C)c(O)c5)c5ccccc45)cc3)ccnc2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)ccc1C
Reaction time: 0.08 h

Procedure:
5-(4-(4-(7-Methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)-2-methylphenol (120 mg, 239 μmol) and cesium carbonate (234 mg, 718 μmol) were combined in DMF and stirred for 5 min. 1-Bromo-2-methoxyethane (66.5 mg, 479 μmol) was added and the mixture was stirred for 1 h. The mixture was then filtered and purified using reverse phase chromatography to provide the titled product. MS: M+H+=560.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:15][Mg]Br.C(OCCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:14])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (75.6 mg, 0.362 mmol) was dissolved in THF (2 mL) under argon and the flask was immersed in ice. Methyl magnesium bromide (1M solution/butyl ether 0.51 mL, 0.507 mmol) was added dropwise while the reaction was cooled in ice. After fifteen minutes at 0° C., the ice bath was removed and the reaction was allowed to stir at room temperature for two hours. 1M Hydrochloric acid was added to quench the reaction and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (3% MeOH/CH2Cl2) to yield the title compound as a clear oil (62.4 mg, 77%). 1H NMR (CDCl3) δ (ppm): 8.18 (s, 1H), 8.06 (m, 1H), 7.50 (m, 2H), 5.32 (m, 1H), 2.69 (d, 1H), 1.76 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([OH:25])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([O:25][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a stirred solution of 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-ol (Example 30) (180 mg, 0.35 mmol) in dichloromethane (10 mL) at 0° C. was added triethylamine (0.08 mL, 0.58 mmol) and methanesulfonyl chloride (0.035 mL, 0.45 mmol) and the mixture stirred 2 hours at 0° C. Ethyl acetate (20 mL) was added and the mixture washed with 2N aqueous hydrochloric acid (20 μL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:iso-hexane (1:1), to afford the desired product (162 mg).
Reaction SMILES: Br.Br.Br[CH2:4][C:5]1[C:6]([NH2:14])=[N:7][C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:4][C:5]2[C:6]([NH2:14])=[N:7][C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=2)[CH2:25][CH2:24]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCCc1ncc(CBr)c(N)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1ncc(CN2CCN(c3ccccc3OC)CC2)c(N)n1
Yield: 19 %

Procedure:
A suspension of 7.0 g (0.020 mol) of 5-bromomethyl-2-propyl-pyrimidin-4-ylamine dihydrobromide, 3.85 g (0.020 mol) of (2-methoxy-phenyl)-piperazine and 6 g (0.043 mol) of dry potassium carbonate in 75 ml of dimethylformamide was dissolved at room temperature for 4 hours. The reaction mixture was suction filtered, the filter cake was washed with ethyl acetate and ethanol, the filtrate was completely freed from the solvents and the residue was chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from hot ethyl acetate. 1.3 g (21%) of 5-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-2-propyl-pyrimidin-4-ylamine were obtained as yellowish crystals, m.p. 130°.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[C:16]([F:26])[CH:15]=2)[CH:7]=1)([CH3:3])[CH3:2].[OH-].[Li+]>C(O)(C)C.O1CCCC1>[CH:1]([O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[C:16]([F:26])[CH:15]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C#Cc2cccc(C(=O)OC(C)C)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cccc(C#Cc2ccc(CC(=O)O)c(F)c2)c1
Reaction time: 0.67 h
Yield: 97.9 %

Procedure:
A solution of 3-(4-ethoxycarbonylmethyl-3-fluoro-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 138, 0.1 g, 0.27 mmol) in isopropanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of lithium hydroxide (1 mL, 2 mmol). After 40 min. at ambient temperature, the reaction mixture was concentrated in vacuo a bit, neutralized with 10% hydrochloric acid and the solid formed was filtered, washed with water and dried to afford the title compound (0.09 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH3:16]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (96 mg, 0.37 mmol), 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (125 mg, 0.40 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (225 mg, 0.48 mmol) in chloroform (4 mL). DIEA (330 μL, 1.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (98 mg, 0.13 mmol, 34%): LC-MS (ES) m/z=535 (M+H)+.