Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:20])[C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:22])([CH3:21])[CH2:11][C:10]2=O.CN1CCCN(C)C1=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:20])[C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:22])([CH3:21])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Reactant: CC(C)[Mg]Cl
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reaction time: 12 h

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 111 mL, 22 mmol), 6-bromo-8-chloro-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 10, 1.5 g, 4.5 mmol), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU, 2.6 mL) in THF was reacted then quenched with 10% HCl, and stored at room temperature for 12 h.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]1[O:18][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=O)CCCC.[OH-].[K+].CO>>[O:18]1[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@@H:9]1[CH2:8][OH:7]
Reactant: CCCCC(=O)OC[C@@H]1O[C@@H]1CCCCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCC[C@H]1O[C@H]1CO
Yield: 90.1 %

Procedure:
3.8 g of (-)-(2S, 3R)-1-valeroxy-2,3-epoxy-8-methylnonane was hydrolyzed with potassium hydroxide/methanol to yield 2.3 g of (-)-(2S, 3R)-2,3-epoxy-8-methyl-1-nonanol.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1.Br[C:39]1[CH:40]=[CH:41][C:42]2[S:46][CH:45]=[CH:44][C:43]=2[CH:47]=1.C(=O)([O-])O.[Na+]>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.O.C(OCC)(=O)C.C(O)C>[S:46]1[C:42]2[CH:41]=[CH:40][C:39]([C:25]3[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])=[C:14]([NH:13][C:12]4[CH:36]=[CH:37][C:9]([F:8])=[CH:10][CH:11]=4)[CH:26]=3)=[CH:47][C:43]=2[CH:44]=[CH:45]1
Reactant: Brc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Nc1ccc(F)cc1
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
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3sccc3c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 1.6 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 79 mg were added ethanol 0.60 mL, water 0.30 mL, 5-bromobenzothiophene 61 mg, sodium hydrogen carbonate 48 mg and tetrakis(triphenylphosphine)palladium(0) 11 mg at room temperature, and it was heated and refluxed for 6 hours. After the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=5:1] to give tert-butyl 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoate. Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoic acid 16 mg of a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH2:17]([N:19](NCCC)[CH2:20][CH3:21])[CH3:18]>C(O)C>[C:8]([C:7]1[C:2]([NH:3][CH2:2][CH2:7][CH2:6][N:19]([CH2:17][CH3:18])[CH2:20][CH3:21])=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Reactant: CCCNN(CC)CC
Solvent: CCO
Product: CCN(CC)CCCNc1ncc(-c2cc[n+]([O-])cc2)cc1C#N

Procedure:
A mixture of 1 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide and 1.35 g diethylamino-1-propylamine in 50 ml ethanol is refluxed for 4 hours. Subsequently, the mixture is concentrated under vacuum and the oil remaining behind is crystallized first from ethanol/diethyl ether and subsequently from methanol. Yield: 1.3 g (90.9% of the theoretical yield), with a melting point of 132° C.-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12](O)[CH3:13]>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH2:12][CH3:13]
Reactant: CCO
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: [Ni]
Product: CCC1C(=O)Nc2ccc(Cl)cc21

Procedure:
The title compound is prepared from 5-chloro-oxindole according to methods known from the literature [B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595]. 1.68 g (0.01 mole) of 5-chloro-oxindole is dissolved in 20 ml of ethanol and 1.0 g of Raney-nickel is added to the solution. The mixture is allowed to react in an autoclave at 110° C. for 36 hours. The catalyst is then filtered off, the solvent is evaporated, and the residue is recrystallized from a mixture of hexane and ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8]CCO.[H-].[Na+].C(O)CO.BrC1C=CC=CC=1CBr>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][OH:8]
Reactant: OCCOCCOCc1ccccc1Br
Agent: BrCc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCOC1
Solvent: OCCO
Product: OCCOCc1ccccc1Br

Procedure:
The reaction and work up was conducted as described in the preparation of compound 415. Starting materials were NaH (60% in oil, 1.8 g, 44 mmol) in THF (160 mL), ethylenglycol (13.4 mL, 240 mmol), 2-bromo-benzyl bromide (10 g, 40 mmol) dissolved in 5 mL dry THF and tetrabutylammonium iodide (0.15 g, 0.4 mmol). The crude product was purified by flash chromatography using DCM/Acetone 30:1 as the eluent to afford the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:31])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C=[N+]([C@@H]2[O:42][C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[Mg+2].[Cl-].C(#N)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:24][CH2:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28]4)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH2:31][OH:42])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1)N1CCS(=O)(=O)CC1
Yield: 18 %

Procedure:
A solution of {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1-thiomorpholin-4-yl)-methanone (44.5 mg, 0.096 mmol) in DMSO (2 mL) was added to a suspension of CYP3A4 (800 nmol)) and NADP in a total volume of 1000 mL reaction buffer (823 mL 0.1M K+ phosphate buffer pH 7.4, 50 mL 1M trisodium citrate, 10 mL 1M magnesium chloride, 2.5 mL 20 mM NADP). The mixture was shaken in a 2 L baffled Erlenmeyer flask at 220 rpm at 27° C. for 4 h, by which time the ratio of substrate:product (12:8 at 3 h, and 11:9 at 4 h) remained almost constant (reaction monitoring: 0.2 mL suspension was treated with 0.2 mL acetonitrile, centrifuged at 13,200 rpm for 2 min, and supernatant was analyzed by HPLC). The suspension (1000 mL) was extracted with 2 L ethyl acetate. The solvent was distilled off and the residue was dissolved in 100 mL water. This was applied to a 10 g reverse phase C18 cartridge which was eluted with a step gradient of acetonitrile in water (15 mL aliquots). Metabolite containing fractions eluting at 35% MeCN were pooled as appropriate and after removal of organic solvent by rotary evaporation were freeze dried to afford the title compound (8.4 mg, 18%) as a white solid. MS: m/e=536.1 [M+CH3COO]−.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:44]([C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[NH:48][CH3:49])[CH3:45]>O.ClCCl>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([N:48]([C:47]1[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=1[O:44][CH3:45])[CH3:49])=[O:9]
Reactant: O=C(O)c1cc(Br)c(Cl)cc1O
Reactant: CNc1ccccc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To a stirring dichloromethane (40 mL) solution containing 5-bromo-4-chloro-2-hydroxybenzoic acid (2.0 g, 8.0 mmol), were added triethylamine (2.2 mL, 16.0 mmol), HATU (4.5 g, 12 mmol) and 2-methoxyl-N-methylaniline (1.19 g, 8.7 mmol). The mixture was stirred at rt for 16 hrs and water was added. The organic layer was separated, washed with NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (300 mg). MS [M+H]+: 371.9; tR=2.60 min (method 1)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([CH2:17][C:18]2[N:22]4[N:23]=[C:24]([CH:27]=[CH2:28])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1>ClCCl.CO.[Pd]>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]2[N:22]([C:18]([CH2:17][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:16]4)=[N:19][N:20]=2)[N:23]=1)[CH3:28]
Reactant: C=Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Reaction time: 3 h

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-4-yl)-6-(6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (22 mg, 0.06 mmol) in dichloromethane (5 mL) and methanol (0.5 mL) under an atmosphere of N2(g) was added 10% palladium on carbon (20 mg) and the atmosphere replaced with H2(g). After stirring vigorously for 3 hours the mixture was filtered through a pad of celite and purified via flash column chromatography (SiO2, CH2Cl2, methanol 0-10%) to return the title compound as a white solid (17 mg, 77%). Analytical data presented in Table 2.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].N[C@](C1C=CC=CC=1)(C)C(OCC)=O>>[NH2:1][C@@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH2:3][OH:4]
Reactant: CCOC(=O)[C@](C)(N)c1ccccc1
Agent: CCOC(=O)[C@@](C)(N)c1ccccc1
Product: C[C@](N)(CO)c1ccccc1

Procedure:
The title compound was prepared by the procedure of Example 445D substituting the product of Example 450B for the product of Example 445C to give a colorless viscous oil (0.57 g, 67%). [α]D23: −13.8°(c=1.05, EtOH). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.28 (s, 3H), 1.76 (br-s, 2H), 3.39 (d, J=5.2 Hz, 2H), 4.72 (t, J=5.2 Hz, 1H), 7.12-7.20 (m, 1H), 7.22-7.32 (m, 2H), 7.44-7.54 (m, 2H). MS ESI+ m/z: 152 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:14]3[C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH:6]=[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=12.[H-].[Na+]>CN(C=O)C>[CH2:23]([N:8]1[C:7]2[CH:6]=[C:5]3[CH:20]=[CH:21][CH:22]=[CH:23][C:4]3=[C:3]([O:2][CH3:1])[C:15]=2[C:14]2[C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:15][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c3cc4ccccc4c(OC)c3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(OC)c3ccccc3cc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 172 %

Procedure:
A solution of 11-methoxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester, (0.458 g, 1.5 mM) in 5 mL DMF was added to a 60% NaH mineral oil dispersion (0.12 g, 3.0 mM, washed twice with hexane) at room temperature. Following cessation of gas evolution, benzyl bromide (0.20 mL, 0.288 g, 1.65 mM) was added and the mixture stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and H2O, the solvent layers separated, and the aqueous layer extracted with ethyl acetate (4×25 mL). The combined ethyl acetate extracts were washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and triturated with hexanes. The resultant yellow-orange gum was purified by column chromatography on silica gel (elution with 9:1 toluene/ethyl acetate) to afford 0.51 g (86%) of the title compound 5-benzyl-11-methoxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester as a yellow-orange foam (MW 395.46).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36]>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CC[C@@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: CCOCCn1c(NC2CCN(CC[C@@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([NH2:12])=[O:11])[N:3]1[O:13]CC1C=CC=CC=1>[Pd].CO>[OH:13][N:3]1[C:2](=[O:1])[N:8]2[CH2:9][C@H:4]1[CH2:5][CH2:6][C@@H:7]2[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2O

Procedure:
1.1 g of the compound obtained in Stage A, 30 ml of methanol and 300 mg of 10% Pd/C are mixed together.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[CH:18][N:17]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (412 mg, 0.574 mmol) was suspended in trifluoroacetic acid (Aldrich redistilled 99+%, 6.0 mL, 78 mmol) and the flask was fitted with a reflux condenser and put in a preheated oil bath (75° C.) and the reaction was stirred overnight. Then, the reaction was cooled to room temperature and concentrated and diluted with saturated sodium bicarbonate and then with 5 N NaOH to raise the pH to about 8-9. The suspension was filtered, and the solid was washed with water. The filtrate was discarded, and the solid was collected with DCM and MeOH, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH. The solid was not >95% pure by HPLC, so the filtrate and solid were combined, concentrated, and purified on a silica gel column (30:1 to 20:1 DCM/MeOH). The fractions with product were collected, concentrated, treated with MeOH, and filtered. The yellow solid was washed with MeOH, collected, and dried under high vacuum at room temperature overnight to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (126.1 mg, 46% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.64 (s, 1H), 8.65 (d, J=2.15 Hz, 1H), 8.36 (d, J=2.35 Hz, 1H), 8.17 (d, J=1.56 Hz, 1H), 8.11 (dd, J=8.90 Hz, 2.25 Hz, 1H), 7.88 (d, J=8.22 Hz, 2H), 7.42 (d, J=7.82 Hz, 2H), 6.78 (d, J=8.80 Hz, 1H), 5.36 (br s, 2H), 4.04 (s, 2H), 3.95 (s, 3H), 3.04 (s, 3H), 2.56 (s, 3H). m/z (ESI, +ve ion) 478 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 ml EtOH was added hydantoin (54 mg, 0.552 mmol) and piperidine (54 μL, 0.552 mmol). The mixture was heated in Microwave (200 W) for 60 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=355)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[NH:30][S:29]1(=[O:35])=[O:34])[O:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14]1)C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[NH:30][S:29]1(=[O:34])=[O:35])[O:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14]1
Reactant: O=C1CN(c2ccc(OC3CCc4ccccc4NC3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CN(c2ccc(OC3CCc4ccccc4NC3=O)cc2O)S(=O)(=O)N1

Procedure:
A solution of 3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenoxy]-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (244 mg) in 30 mL of EtOH/HOAc (2:1) is hydrogenated at 1 atm over Pd/C (100 mg) for 4 h. The catalyst is filtered and the filtrate evaporated. The residual solid is triturated with ether to give the title compound: (M−1)−=402.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[H-].[Na+].CN(C=O)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1>C1C=CC=CC=1.ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:8][C@@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: CN1CCC(O)C(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 7.65 g of 1-methyl-3-phenyl-4-piperidinol (approximately a 50:50 mixture of isomers) of Example 1 in 100 ml of benzene is added to a suspension of 1.2 g of sodium hydride in 50 ml dry benzene. The mixture is heated to reflux, and 25 ml of dry DMF are added dropwise over a 10-minute period. After refluxing for 1 hour, the mixture is cooled to room temperature and a solution of 6.53 g of p-chlorofluorobenzene in 50 ml of benzene is added all at once. After stirring for 18 hours at room temperature, 100 ml of DMF are added and the mixture is refluxed for 5 hours, then stirred for 18 hours at room temperature and then refluxed an additional 4 hours. The mixture is partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether. The combined extracts are washed with water, saturated aqueous NaCl solution and dried over anhydrous MgSO4. Removal of the solvent in vacuo affords an oil. This material is dissolved in dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed with saturated aqueous NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford an oil which crystallizes on standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. A pure product, trans-4-(4-chlorophenoxy)-1-methyl-3-phenylpiperidine, is thus obtained, m.p. s 83.5°, 84.5°-87° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:62]2[C:67](=[O:68])[NH:66][C:65](=[O:69])[C:64]([C:70]#[N:71])=[N:63]2)[CH:45]=[C:46]([Cl:61])[C:47]=1[O:48][C:49]1[CH:54]=[C:53]([CH:55]([CH3:57])[CH3:56])[C:52](=[O:58])[N:51]([CH2:59]O)[N:50]=1>C(Cl)Cl>[Cl:61][C:46]1[CH:45]=[C:44]([N:62]2[C:67](=[O:68])[NH:66][C:65](=[O:69])[C:64]([C:70]#[N:71])=[N:63]2)[CH:43]=[C:42]([Cl:41])[C:47]=1[O:48][C:49]1[CH:54]=[C:53]([CH:55]([CH3:56])[CH3:57])[C:52](=[O:58])[N:51]([CH2:59][O:10][C:9](=[O:11])[CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:50]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)Cc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.4 %

Procedure:
A solution of pyridin-3-yl-acetic acid hydrochloride salt (57.3 mg, 0.33 mmol) in methylene chloride (1.84 mL) was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (119 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.99 mmol). The resulting solution was stirred at 25° C. for 2.5 h. At this time, 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.42 mmol) was added to the reaction. The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (3×150 mL). The organics were dried over sodium sulfate, filtered, rinsing with methylene chloride and concentrated in vacuo. Biotage flash chromatography (40S, 1-4% methanol/methylene chloride) followed by supercritical fluid chromatography (Daicel OD column, 60% methanol) afforded pyridin-3-yl-acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (43.2 mg, 22%) as a yellow solid. ES+-HRMS m/e calcd for C25H19N7O6Cl2 (M+H+) 584.0847, found 584.0848.