Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(C)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a solution of 2,4-dichloropyrimidine (3.8 g, 25.5 mmol) in THF (175 mL) was added Pd(PPh3)2Cl2 (1.8 g, 2.6 mmol), CuI (247 mg, 1.3 mmol), and TEA (10.7 mL, 76.5 mmol) and the mixture was heated to 60° C. A solution of N-(5-ethynyl-2-methylphenyl)-2,2,2-trifluoroacetamide (6.4 g, 28 mmol) in THF (75 mL) was added through an addition funnel over 60 min. After 16 h, the dark reaction was concentrated onto silica gel and purified by column chromatography. Fractions containing product were concentrated and the impurity was triturated with DCM. The remaining liquid was purified again by column chromatography to give the desired product (2.7 g, 31%). 1H NMR (400 MHz, d6-DMSO) δ 11.09 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J=8.0 and 1.6 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 2.24 (s, 3H) ppm.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl>CS(C)=O>[C:1]([N:9]1[CH2:10][CH2:11][C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To 10.7 g (26 mmoles) crude ethyl 1-benzoyl-4-(phenylmethyl)-4-piperidinecarboxylate was added a solution of 14.6 g (130 mmoles) potassium tert-butoxide in 130 ml dimethyl sulfoxide. The resulting purple solution was stirred 2 hours to give a dark orange solution. The solution was poured into 500 ml rapidly stirred ice-water and acidified with 12 ml concentrated hydrochloric acid. The resulting white precipitate was filtered off, washed with 3×20 ml cold water, then dissolved in 200 ml ether. The ether solution was washed with 3×20 ml water, and brine, dried, and the solvent was removed in vacuo to give a pale yellow foam. The product was recrystallized from ether to give 6.63 g (75%) product, m.p. 183°-189° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](Br)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccc(O)cn1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C)nc1
Yield: 48.4 %

Procedure:
A mixture of 11.0 g (0.10 mol) of 5-hydroxy-2-methylpyridine (commercially available), 13.8 g (0.10 mol) of n-butyl bromide and 6.00 g (0.04 mol) of anhydrous potassium carbonate with 100 ml of acetone was refluxed for 24 hours, the solvent was removed, 100 ml of water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:4) to give 8.00 g of an oily product (yield 47.9%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].Cl[CH2:13][C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(OCC)(=O)C>CN(C)C=O>[CH:17]([O:16][C:14]([CH2:13][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:15])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
4 g (42.06 mmol) of 4-hydroxypyridine was dissolved in 80 ml of N,N-dimethylformamide, and 8.7 g (62.92 mmol) of pottasium carbonate and 16.45 g (63 mmol) of benzhydryl α-chloroacetate were added thereto. After stirring for 4 hours at 60° C., 200 ml of ethyl acetate was added to the reaction solution, and washed with water and a saturated sodium chloride aqueous solution followed by drying over anhydrous sodium sulfate and treating with active carbon. The solvent was distilled off under reduced pressure, and the crystal residue was washed with ether to obtain 9.8 g (yield: 73%) of 1-benzhydryloxycarbonylmethyl-4-pyridone.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:24])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)[C:5]1=[O:23].CS(O[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1([CH3:24])[N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:45])([F:46])[F:47])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)[C:5]1=[O:23]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Yield: 72 %

Procedure:
NaH (at 60%) (44 mg, 1.1 mmole), is added under argon to a solution of 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-imidazolidine-2,4-dione (317 mg, 1 mmole) in anhydrous DMF (8 ml). A release of gas accompanies the change in colour of the reaction medium which becomes orange. Stirring is maintained for 1 hour at 23° C. before adding 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate (prepared according to an experimental protocol described in WO 2005077968) (332 mg, 0.8 mmole). After reaction for 15 hours, the reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: CH2Cl2/AcOEt: 1/1 to 0/1). The expected compound is obtained in the form of a pale yellow oil with a yield of 72% (364 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole (72 mg, 0.21 mmol) from Example 32, Step C (lower Rf isomer) in THF (3 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.160 mL, 0.26 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.045 mL, 42 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([O:11][CH3:12])[C:6]=2[C:5]([CH:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@H:16]([O:35]CC3C=CC=CC=3)[C@@H:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=[CH:4][C:3]=1[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH3:61])=[CH:55][CH:54]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([O:11][CH3:12])[C:6]=2[C:5]([C@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@H:16]([OH:35])[C@@H:15]([CH2:43][OH:44])[O:14]2)=[CH:4][C:3]=1[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH3:61])=[CH:55][CH:54]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3OC)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.8 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-3-methoxy-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (124 mg, 0.147 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (12 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (38 mg, 54%) as a white solid.
Reaction SMILES: O1CCCC1.[H-].[Na+].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[C:17]1[CH:18]=[C:19]([CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1)[CH2:20][N:21]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[CH:47][C:46]=1[O:54][CH3:55])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][N:23]=1>[Cl-].[Na+].O>[CH2:8]([O:15][C:17]1[CH:18]=[C:19]([CH:56]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:58]=1)[CH2:20][N:21]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[CH:47][C:46]=1[O:54][CH3:55])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:24][N:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
To tetrahydrofuran (6 ml) is added sodium hydride (60%) (390 mg) under nitrogen atmosphere, followed by an addition dropwise of benzyl alcohol (1.01 ml) under water-cooling, and the mixture is stirred at the same temperature for 30 minutes. To this reaction mixture is added a mixture of (3-fluoro-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (430 mg) and tetrahydrofuran (4 ml) and the mixture is stirred under nitrogen atmosphere at 70° C. overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=97:3→17:3) to give (3-benzyloxy-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (221 mg). MS (m/z): 751 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:12]1.S([O-])(O[O-])(=O)=O.[K+].[K+]>CCCCCCC.CC(C)=O.O.COC(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:12])[CH:5]=[N:4][C:3]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: Clc1cccnc1C1CC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: Oc1cnc(C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
A round bottom flask was charged with 3-chloro-2-cyclopropylpyridine (Preparation 36, 0.475 g; 3.092 mmol), bis(pinacolato)diboron (0.980 g, 3.86 mol) and 4,4-di-tert-butyl-2,2-dipyridyl (0.025 g; 0.093 mmol) in heptane (1.55 L). The reaction mixture was cycled between vacuum and nitrogen 6 times over 15 minutes. Di-μ-methanolatodiiridium(Ir—Ir)-cycloocta-1,5-diene (1:2) (0.063 g; 0.093 mmol) was then added and the reaction stirred for 18 hours under nitrogen atmosphere at room temperature. The reaction mixture was evaporated to dryness to afford a red viscous oil. The resulting oil was dissolved in acetone (10.0 mL) and cooled to 0° C. with an ice bath. Then potassium peroxymonosulfate (2.55 g, 4.15 mmol) in water (10.0 mL) was added dropwise to the mixture and stirred at this temperature for 1 hour. The reaction was then diluted in tert-butyl methyl ether (25.0 mL) and washed with brine (3×25.0 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound as a pale yellow solid (0.220 g, 1.28 mmol, 42%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C1CCCCC1.CCOC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: COc1ccc(B(O)O)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Yield: 69.2 %

Procedure:
According to Scheme 5 Step 1: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 17.2 mmol, 3.00 g, Example 1 Step 1) and 4-methoxyphenylboronic acid (1.5 eq, 25.9 mmol, 3.93 g) according to the procedure described for Example 2 Step 2. Reaction conditions: 4.5 hours at 120° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using pure AcOEt then AcOEt/MeOH 95/5 as eluent to afford 5-(4-methoxyphenyl)-(1H)-pyridin-2-one (11.9 mmol, 2.40 g, 69%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[N:12][CH:11]=[N:10]1.[C:16]([Cu])#[N:17].FC1C=CC(C#N)=C(N2C=CC=N2)C=1>CN(C=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13]([CH2:14][OH:15])=[N:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: N#C[Cu]
Reactant: OCc1ncnn1-c1cc(F)ccc1Br
Agent: N#Cc1ccc(F)cc1-n1cccn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1ncnc1CO
Yield: 48 %

Procedure:
This compound was prepared from (2-(2-bromo-5-fluorophenyl)-2H-1,2,4-triazol-3-yl)methanol and CuCN in DMF at 125-130° C. for 5 h by the method used for the preparation of 4-fluoro-2-pyrazol-1-yl-benzonitrile. Yield: 48% (beige solid) HPLC rt=1.11 min. LC/MS m/z 219 (M+H). 1H NMR (CDCl3, 500 MHz) δ ppm 2.39 (1H, br.s, OH), 4.79 (2H, s, 9-OCH2), 7.32-7.40 (1H, m, 5-CH), 7.50 (1H, d, J=8.2, 2.1 Hz, 3-CH), 7.87 (1H, dd, J=8.5, 5.5 Hz, 6-CH), 8.14 (1H, s, 9-CH). HRMS (ESI) calcd for C10H8FN4O (M+H) 219.0682; found 219.0689 (δ+3.1 ppm).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:28]3[CH:29]=[C:24]([CH2:23][OH:22])[CH:25]=[CH:26][CH:27]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: OCc1cccc(B(O)O)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3cccc(CO)c3)nc3scnc23)cc1OC
Temperature: 90 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
A mixture of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.62 mmol), 3-(hydroxymethyl)phenylboronic acid (104 mg, 0.68 mmol), Pd2(dba)3 (71 mg, 0.12 mmol), X-Phos (118 mg, 0.25 mmol), Na2CO3 (131 mg, 1.2 mmol) in dioxane (20 mL) and H2O (5 mL) was heated to 90° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by column chromatography (MeOH:DCM=1:80) to give (3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)methanol (51 mg, 21%) as yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H), 8.49 (s, 1H), 8.42 (d, 1H, J=6.9 Hz), 7.97 (s, 1H), 7.87 (s, 1H), 7.49-7.46 (m, 2H), 7.18 (dd, 1H, J1=8.7 Hz, J2=2.7 Hz), 6.93 (d, 1H, J=8.4 Hz), 4.79 (s, 2H), 4.00 (s, 3H), 3.93 (s, 3H). LC-MS: 395 [M+H]+, tR=1.48 min. HPLC: 98.36% at 214 nm, 98.69% at 254 nm, tR=6.086 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[N:17][OH:18])[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: COc1cccc(C2CCCCC2=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C2CCCCC2=NO)c1

Procedure:
2-(3-Methoxyphenyl)-cyclohexanone, as described in Step A above, (0.61 g, 3 mmol), hydroxylamine hydrochloride (0.40 g, 6 mmol) and sodium acetate (0.80, 6.2 mmol) were combined in EtOH (4 mL): H2O (2 mL) and heated at reflux for 3 h. The reaction mixture was concentrated, then partitioned between EtOAc (100 mL) and H2O (100 mL), the organic layer separated, washed with H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:30])[CH2:10]1)=[O:7])(C)[CH3:4].CC[C@@H](C(O[C@@H]1[C@@H]2[C@@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@@H](C)C=CC2=C[C@@H](O)C1)=O)C.CC(N1C(/C=C/[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C2C=CC(F)=CC=2)C2C=CC=CC1=2)C.[Na+]>>[CH3:1][CH2:2][C@@H:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:30])[CH2:10]1)=[O:7])[CH3:4]
Reactant: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Agent: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: [Na+]
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21

Procedure:
simvastatin (Zocor); pravastatin (Pravachol); fluvasatin (Lescol).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:4]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4]3)=[O:10])[CH2:12]2)[O:29][N:31]=1
Reactant: COCCC(N)=NO
Reactant: COC1CCCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)C1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCCC(OC)C3)C2)n1

Procedure:
250 mg (0.434 mmol, 72% pure) of 1-[(3-methoxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 207A) and 75.3 mg (0.478 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 1. Yield: 105 mg (48% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N+:26]([O-])=O)[C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10]1)#[N:2].[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:26][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([C:1]#[N:2])[C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10]1
Reactant: N#Cc1cncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cncc(N)c1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
A mixture of benzyl [(3S)-1-(3-cyano-5-nitropyridin-4-yl)piperidin-3-yl]carbamate (0.065 g, 0.17 mmol), iron (0.084 g, 1.5 mmol), and ammonium chloride (0.091 g, 1.7 mmol) in EtOH (2 mL) and water (0.2 mL) was stirred at 85° C. for 15 min. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOH. The filtrate was concentrated under reduced pressure and the residue was partitioned between water and EtOAc. The organic fraction was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the sub-title compound (0.055 g). LCMS (ESI) calc. for C19H22N5O2 m/z=352.2 [M+H]+. found 352.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[NH:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)[CH:3]=1)=[O:36]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
To a solution of 3-(3-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (12.2 mg, 0.042 mmol) in 0.9 mL THF was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0066 mL, 0.046 mmol) and the reaction stirred at rt. After 15 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. At 40 min the reaction was quenched with 1 mL MeOH, evaporated, and chromatographed eluting with 2% to 5% MeOH/CHCl3 gradient. The resulting solid was triturated with 40% EtOAc/hexane to give the title compound as a light tan solid (9.9 mg, 48%). 1H NMR (Acetone-d6) δ: 9.54 (br. s, 1H), 8.77-8.81 (m, 1H), 8.66 (s, 1H), 8.34 (d, J=2.9 Hz, 1H), 8.09-8.13 (m, 1H), 7.29-7.54 (m, 6H), 7.03-7.12 (m, 3H), 4.41 (ddd, J=12.9, 4.4, 2.9 Hz, 1H), 3.81-3.90 (m, 1H), 3.56-3.70 (m, 2H), 3.02-3.14 (m, 1H).