Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14](O)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:53])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14]([Cl:53])[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(O)c1nccs1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(Cl)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To (2R,5R)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-(hydroxy-thiazol-2-yl-methyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.076 g, 0.13 mmol) and triethylamine (36 μL, 0.3 mmol) in DCM (0.6 mL) cooled with an ice bath under nitrogen was added methanesulfonyl chloride (12 μL, 0.2 mmol). The reaction was stirred at this temperature for 1 h and then warmed room temperature for 18 h. Saturated aqueous sodium bicarbonate was added and the mixture extracted with EtOAc. The combined organics were washed with brine, dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.03 g). MS: [M+H]+=612.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][N:10]=1>>[CH2:15]([C:12]1[CH:11]=[N:10][C:9]([N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH3:16]
Reactant: O=C1CCNCC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(=O)CC2)nc1

Procedure:
The title compound was synthesized from piperidin-4-one and 2-chloro-5-ethylpyrimidine manner similar to that described in Example 9.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([F:18])[CH:11]=2)=[N:21][CH:22]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Brc1ccc(Br)nc1
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: CCO
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccc(Br)cn2)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 76.7 %

Procedure:
(4-Benzyloxy-3-fluorophenyl)boronic acid (1.06 g, 4.22 mmol) was added to a suspension of 2,5-dibromopyridine (1.0 g, 4.22 mmol) in toluene (8 mL), followed by addition of 2M Na2CO3 (6 mL) and Pd(PPh3)4 (0.15 g, 0.13 mmol) and EtOH (2 mL). The reaction mixture was degassed with N2 and heated at 90° C. overnight. The mixture was cooled to ambient temperature, water was added, and the mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, filtered through a pad of silica gel, and the filtrate was concentrated to give a solid, which was recrystallized from MeOH to give 1.16 g (77%) of 5-bromo-2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}pyridine as a faint yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.69 (d, 1H, J=2.2 Hz), 7.85 (dd, 1H, Ja=8.4 Hz, Jb=2.1 Hz), 7.77 (dd, 1H, Ja=12.4 Hz, Jb=2.1 Hz), 7.67 (d, 1H, J=8.6 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.50-7.30 (m, 5H), 7.07 (t, 1H, J=8.4 Hz), 5.20 (s, 2H); LRMS (ESI), m/z 358/360 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=4[C:16]=3[CH2:17][CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=4[C:16]=3[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)COc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1Br
Yield: 47.4 %

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-({1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthyl}oxy)acetate (0.180 g, 0.345 mmol) was hydrolyzed with potassium hydroxide (0.077 g, 1.4 mmol) in THF (5 mL) and water (5 mL). Crystallization from acetonitrile and drying for 12 hours at 80° C. yielded 2-({1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthyl}oxy)acetic acid as a cream-colored solid (0.0807 g), mp 155-156° C. Mass spectrum (−ESI, [M−H]−) m/z 491; 1HNMR (500 MHz, DMSO-d6): δ13.0-13.5 (br s, 1H), 8.35 (d, 1H, J=1.2 Hz), 8.25 (d, 1H, J=8.9 Hz), 8.10 (d, 1H, J=9.0 Hz), 8.05 (dd, 1H, J=9.0 Hz and 1.7 Hz), 7.7 (d, 1H, J=7.8 Hz), 7.6 (d, 1H, J=7.9 Hz), 7.45 (d, 1H, J=9.2 Hz), 7.35-7.4 (m, 1H), 7.30-7.35 (m, 1H), 5.0 (s, 2H), 3.0 (t, 2H, J=7.9 Hz), 1.8-1.9 (m, 1H), 1.7-1.8 (m, 4H), 1.5-1.6 (m, 2H), 1.4-1.5 (m, 2H), and 1.15-1.25 ppm (m, 2H). Elemental Analysis for C27H25BrO4: Calculated: C, 65.13; H, 5.16; N, 0.00. Found: C, 64.83; H, 4.94; N, 0.06.
Reaction SMILES: CO[CH:3]=[CH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+]>OS(O)(=O)=O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:5](=[O:6])[CH:4]=[CH:3]3)[CH2:19][CH2:18]1)=[O:31]
Reactant: COC=CC(=O)Nc1ccc(N2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)N2CCN(c3ccc4[nH]c(=O)ccc4c3)CC2)cc1OC
Temperature: 25 °C
Yield: 5 %

Procedure:
N-(β-methoxyacryloyl)-p-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]aniline (5 g) was added portionwise to 50 ml of 60% H2SO4 while stirring at room temperature. After continuing the reaction for 2 hours, the reaction mixture was neutralized with 10 N NaOH to precipitate crystals which then were collected by filtration and washed with water. Recrystallization of the crystals from chloroform-methanol gave 230 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]carbostyril, m.p. 265°-266.5° C. (decomp.), yellow granules.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:8])[CH:7]=1.[SH:10][CH2:11][CH2:12][OH:13]>C(O)C>[OH:13][CH2:12][CH2:11][S:10][C:4]1[C:3](=[O:9])[C:2]([CH3:1])=[CH:7][C:6](=[O:8])[CH:5]=1
Reactant: CC1=CC(=O)C=CC1=O
Reactant: OCCS
Solvent: CCO
Product: CC1=CC(=O)C=C(SCCO)C1=O
Temperature: 0 °C

Procedure:
Methyl-p-benzoquinone 12.2 g, 0.1 mole) and 2-mercaptoethanol (3.9 g, 0.05 mole) are mixed in absolute ethanol (70 ml) under nitrogen and with stirring. The temperature rises to 50° C. The mixture is cooled in a bath of ice-water and left to stand, with stirring, for 2 hours at ambient temperature. The solution is concentrated under vacuum and the oil obtained is chromatographed on Silica 60 (eluent: dichloromethane). According to 1H and 13C NMR, a first fraction (3 g) is a 50/50 mixture of two products: 2-hydroxyethylthio-5-methyl-1,4-benzoquinone and 2-hydroxyethylthio-6-methyl-1,4-benzoquinone. A second fraction gives the expected product:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35](=[O:48])OC3C(F)=C(F)C(F)=C(F)C=3F)[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:57][O:58][C@@H:59]([C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1)[C@@H:60]([CH3:64])[C:61]([OH:63])=[O:62].C(N(C(C)C)CC)(C)C>ClCCl>[CH:5]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35]([N:66]3[CH2:67][CH2:68][CH2:69][C@H:65]3[C@H:59]([O:58][CH3:57])[C@H:60]([C:61]([OH:63])=[O:62])[CH3:64])=[O:48])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 92 %

Procedure:
The above reaction and purification were repeated in a similar fashion using #104 (2.60 g, <3.35 mmol, 1 eq.), #103 (750 mg, 3.35 mmol, 1 eq.), dichloromethane (10 mL, 0.3 M) and diisopropylethylamine (1.35 mL, 7.73 mmol, 2.3 eq.) to give #105 (2.4 g, 92%) as a tan foam. Fractions containing impure product (1.7 g) were combined with the previous impure fractions and purified as described above to afford additional #105 (1.30 g, quantitative yield for both reactions over two steps). LC-MS: m/z 779.3 [M+H+], 802.3 [M+Na+], retention time=1.05 minutes.
Reaction SMILES: [C:1]([N:16]([CH3:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:23]([CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30]O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:23]([CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30][O:20][C:19](=[O:21])[CH2:18][CH2:17][N:16]([C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)O
Reactant: CCCCCCCCC(CO)CCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)OCC(CCCCCC)CCCCCCCC
Yield: 74.2 %

Procedure:
N-Myristoyl-N-methyl-β-alanine (55 g; manufactured by Kawaken Fine Chemicals Co., Ltd.) and 45 g of 2-hexyldecanol were charged in a 500-ml flask, and thereto was added 2 g of p-toluenesulfonic acid as the catalyst. The mixture was subjected to a reaction at 130° C. for 5 hours. After completion of the reaction, the reaction mixture was neutralized with 1.6 g of an aqueous solution (50%) of sodium hydroxide, the aqueous layer was removed therefrom, the residue was washed with 100 g of deionized water and dehydrated under the condition of 60 mmHg and 95-105° C., and the insoluble substances were filtered off with a filter paper to give 70 g of an oily product as the filtrate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.O>C(OC(C)C)(C)C.CCCCCC.[Ni](Br)Br>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Nc3ccc([N+](=O)[O-])cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Br[Ni]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Nc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of the compound obtained in Example 219 (162 mg, 0.26 mmol) in methanol/THF (1/1, 10 mL) were added nickel bromide (II)(5.7 mg) and sodium borohydride (40 mg, 1.1 mmol), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added ethyl acetate (20 mL) and water (20 mL), and the insolubles were filtered off with Celite. The organic layer was washed with saturated aqueous solution of sodium chloride (10 ml), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (alumina 2 g, ethyl acetate/methanol=1/0 to 10/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (99 mg, 0.17 mmol, Yield 64%) as pale yellow amorphous substance.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])N=N[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](N1CCCC1)=[CH2:26]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:26]=[CH:25][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(C)cc2)c(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(C)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure D, ethyl 5-phenyl-6-p-tolyl-1,2,4-triazine-3-carboxylate (Compound 12, 177 mg, 0.56 mmol) and crude 1-vinylpyrrolidine (Compound 38, 730 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Brc1cnc2ncccn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2ncccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromoimidazo[1,2-α]pyrimidine (500 mg, 2.5 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (1.39 ml of a 2.0M solution in tetrahydrofuran, 2.78 mmol). After stirring for 5 min tri-n-butyltin chloride (0.8 ml, 2.90 mmol) was added and the reaction stirred for 10 min at −78° C. then allowed to warm to ambient temperature to give a solution of 3-tributylstannylimidazo[1,2-α]pyrimidine in tetrahydrofuran: m/z (ES+) 407, 409, 411 (M++H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])=[C:7]([CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9].[OH:40]OS([O-])=O.[K+].[NH4+].[OH-]>CC#N.C(Cl)Cl.CO.O.C(Cl)Cl>[CH2:36]([NH:35][C:33](=[O:34])[NH:32][C:6]1[CH:5]=[CH:4][C:3]([S:2]([CH3:1])=[O:40])=[CH:31][C:7]=1[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14][CH2:13]1)=[O:9])[CH2:37][CH2:38][CH3:39]
Reactant: O=S([O-])OO
Reactant: CCCCNC(=O)Nc1ccc(SC)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCCCNC(=O)Nc1ccc(S(C)=O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 5-methylthio-2-(N'-n-butylureido)-N-[(1-diphenylme-thylpiperidin-4-yl)methyl]benzamide (EXAMPLE 73) (200 mg, 0.367 mmol) in CH3CN/CH2Cl2 /MeOH/H2O (10 ml/2 ml/4 ml/0.5 ml) was agitated with OXONE® (2KHSO5KHSO4K2SO4) (142 mg, 0.231 mmol) for 2 hours at room temperature and then an additional OXONE® (15 mg) was added. The reaction mixture was made basic with 25% NH4OH and diluted with CH2Cl2. The organic layer was washed twice with H2O, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel to give 2-(N'-n-butylureido)-5-methylsulfinyl-N-[(1-diphenylmethylpiperidin-4yl)methyl]benzamide. 130 mg (63%): mp 209°-211° C.; 1H NMR (CDCl3) ppm: 0.91 (3H, t), 1.33-1.88 (11H, m), 2.69 (3H, s), 2.88 (2H, m), 3.22-3.31 (4H, m), 4.24 (1H, s), 4.85 (1H, bt), 7.03 (1H, bt), 7.13-7.42 (11H, m), 7.91 (1H, d), 8.63 (1H, d), 10.71 (1H, s); and 2-(N'-n-butylureido)-5-methylsulfonyl-N-[(1-diphenylmethylpiperidin-4-yl)-methyl]benzamide, 30 mg (14%): mp 178°-179° C.; 1H NMR (CDCl3) ppm: 0.93(3H, t), 1.31-1.88 (11H, m), 2.90 (2.90 (2H, m), 3.02 (3H, s), 3.23-3.34 (4H, m), 4.25 (1H, s), 4.79 (1H, bt), 6.61 (1H, bt), 7.13-7.40 (10H, m), 7.89 (1H, dd), 7.97 (1H, d), 8.73 (1H, d), 10.82 (1H, s), respectively.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11]2C=CC=N[C:10]=2[CH2:9][N:8](C2CCN(C(OC(C)(C)C)=O)CC2)[C:7]1=[O:29].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39].[NH:8]1[CH:9]=[CH:10][CH:11]=[N:6][C:7]1=[O:29]
Reactant: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3ncccc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=c1nccc[nH]1
Reaction time: 8 h

Procedure:
tert-Butyl 4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (0.10 g, 0.21 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight. The reaction was concentrated to afford the bis-TFA salt of the title compound (0.048 g). MS 233.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+].Cl[C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([C:51]3[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:54]=[CH:53][N:52]=3)[CH2:47][CH2:46]2)[N:42]=[C:41]([N:61]2[CH2:65][CH2:64][CH2:63][CH:62]2[CH3:66])[N:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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>[CH3:12][N:8]1[CH2:7][C:6]([CH3:14])([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([C:39]3[CH:44]=[C:43]([N:45]4[CH2:50][CH2:49][N:48]([C:51]5[C:56]([C:57]([F:58])([F:59])[F:60])=[CH:55][CH:54]=[CH:53][N:52]=5)[CH2:47][CH2:46]4)[N:42]=[C:41]([N:61]4[CH2:65][CH2:64][CH2:63][CH:62]4[CH3:66])[N:40]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CC1CCCN1c1nc(Cl)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Reactant: CN1Cc2cc(Br)ccc2C(C)(C)C1
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: CC1CCCN1c1nc(-c2ccc3c(c2)CN(C)CC3(C)C)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 25 °C

Procedure:
To a mixture of 7-bromo-2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinoline (140 mg, 0.55 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (140 mg, 0.55 mmol), DPPF (9 mg, 0.017 mmol), and KOAc (162 mg, 1.65 mmol) in DMSO, add PdCl2(DPPF)-DCM complex (13 mg, 0.0165 mmol). Purge the reaction mixture for 10 minutes with dry N2. Heat the stirring reaction mixture overnight at 80° C. Cool to room temperature. Add 4-chloro-2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (141 mg, 0.33 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol), and Cs2CO3 (162 mg, 0.50 mmol). Heat the stirring reaction mixture overnight at 80° C., cool to room temperature, and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with DCM:MeOH (9:1) to afford 2,4,4-trimethyl-7-{2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-isoquinoline. 1H NMR (400 MHz, CDCl3): δ 1.30 (m, 9H, 3×CH3); 1.68 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.05 (m, 2H, CH2CH2); 2.40 (s, 2H); 2.43 (s, 3H, NCH3); 3.39 (m, 4H); 3.61 (s, 2H); 3.67 (m, 2H); 3.79 (m, 4H); 4.34 (m, 1H); 6.27 (s, 1H, Ar—H); 7.01 (m, 1H); 7.35 (m, 1H); 7.63 (s, 1H); 7.88 (m, 1H); 7.88 (m, 1H); 8.44 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:27]=1)[CH2:5][P:6]([CH:11]([NH:15]C(OCC1C=CC=CC=1)=O)[CH:12]([CH3:14])[CH3:13])([O:8][CH2:9][CH3:10])=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:41])[CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH:27]=1)[CH2:5][P:6]([CH:11]([NH2:15])[CH:12]([CH3:13])[CH3:14])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(N)C(C)C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
To a solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (10.6 g, 18.0 mmol) in 200 mL methanol was added Pd/C (10%) (2.1 g). The reaction mixture was hydrogenated in H2 (50 psi) for 2 to 3 hours. The catalyst was filtered over a celite pad. The solvent was removed in vacuo to afford 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-amino-2-methylpropyl)(ethoxy)-phosphinoyl)propanoic acid methyl ester (7.1 g, 15.6 mmol, 87%) as white solid, NMR (DMSO-d6) 0.80-0.91 (m, 6), 1.05-1.18 (m, 3), 1.37 (s, 9), 1.46 (m, 1), 1.90 (m, 1), 2.00-2.20 (m, 1), 2.56-2.64 (m, 1), 3.56 (s, 3), 3.70-3.95 (m, 3), 4.08 (d, 2), 7.10-7.20 (3, m), 7.24 (m, 1), 7.38 (t, 1) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(CC)CC>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:28][CH2:27]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccccc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 18.9 mg (0.07 mmol) 2-Morpholin-4-yl-5-nitro-benzoyl chloride, 16.5 mg (0.084 mmol) 1-(2-Chloro-phenyl)-piperazine and 34 ul (0.245 mmol) NEt3 in 2 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 2 ml CH3CN/MeOH/HCOOH 2/2/1 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 23.2 mg (77%) of the title compound. MS (m/e): 431.2 (MH+, 100%)