Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:4]=1.[CH2:22]([N:24](CC)[CH2:25]C)C.CNC>CCCCCC.CC(C)=O>[CH3:22][N:24]([CH3:25])[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:4]=1
Reactant: CCC(CC)Nc1nc(SC)nc(NC(C)C)c1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCC(CC)Nc1nc(N(C)C)nc(NC(C)C)c1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
15.6 g of 2-methylmercapto-4-isopropylamino-5-nitro-6-(3-pentyl-amino)-pyrimidine (0.05 mol) are dissolved in 250 ml of alcohol. Then 20 ml of triethylamine and 3 g of dimethylamine are added. The reaction mixture is kept for 16 hours under high pressure (12 bar) at 100° C, until no more starting material can be detected in a thin-layer chromatogram (silica gel. hexane/acetone 5:1). The mixture is evaporated, the residue is treated with water and extracted twice with ether. The ethereal extracts are dried over MgSO4, filtered and evaporated, to yield 13.5 g of 2-dimethylamino-4-isopropylamino-5-nitro-6-(3-pentylamino)-pyrimidine; b.p. 160° C/0.001 Torr.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1>>[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[CH:43][CH:44]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(N)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-aminopyridine-5-boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=513, obsd.=513).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:17]([N:19]2C=N[CH:21]=[CH:20]2)=[O:18])C=1.[Cl:24][C:25]1[CH:38]=[CH:37][C:28]([O:29][C:30]2[CH:36]=CC(N)=[CH:32][CH:31]=2)=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:17]([NH:19][C:20]2[CH:21]=[CH:36][C:30]([O:29][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:38][CH:37]=3)=[CH:31][CH:32]=2)=[O:18])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccnc(N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(NC(=O)Nc2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9 %

Procedure:
A solution of 4-tert-butyl-2-aminopyridine (0.177 g, 1.18 mmol, 1 equiv.) in 1.2 mL of anh. CH2Cl2 (1.2 mL) was added to CDI (0.200 g, 1.24 mmol, 1.05 equiv) and the mixture was allowed to stir under argon at room temperature 1 d. To the resulting solution was added 4-(4-chlorophenoxy)aniline (0.259 g, 1.18 mmol, 1 equiv.) in one portion. The resulting mixture was stirred at room temperature for 1 d, then was treated with a 10% citric acid solution (2 mL) and allowed to stir for 1 h. The resulting organic layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was treated with CH2Cl2 (10 mL) and a 1 N aqueous NaOH solution. This mixture was allowed to stir overnight. The resulting organic layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were (MgSO4) and concentrated in vacuo. The resultant solids were suspended in diethyl ether (10 mL) and sonicated for 15 minutes. The resulting white solids were dried to give N-(4-tert-butylpyridyl)-N′-(4-(4-chlorophenoxy)phenyl) urea (42 mg, 9%): mp 198-199° C. B3. Reaction of Substituted Aniline with N,N′-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine
Reaction SMILES: [CH:1]1([N:7]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16]C)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.CCO.O>[CH:1]1([N:7]([CH2:18][CH:19]2[CH2:20][CH2:21]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of methyl 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylate (Intermediate 12, 4.14 g; 14.3 mmol) in THF/EtOH/H2O (3/2/1, 120 ml) was treated with an aqueous solution of lithium hydroxide monohydrate (42.9 ml; 1.00 M; 42.9 mmol) at ambient temperature. After 1 hour, the organic solvents were evaporated in vacuo, the remaining aqueous layer was acidified with HCl (1 N) until pH=6 and extracted with DCM (4×50 ml). The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as an off-white solid (3.64 g, 92.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[C:3]([CH3:20])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCC(O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-3-(4-hydroxypiperidin-1-yl)-2-methoxy-4-methylphenyl]ethanone (15 mg, 0.050 mmol), ammonium acetate (39 mg, 0.50 mmol) and sodium cyanoborohydride (6 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (7 mg, 50%). LCMS calculated for C15H24ClN2O2 (M+H)+: m/z=299.1. found: 299.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.O>CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:9][CH:10]=[CH2:11])[CH2:12][C:13]([OH:21])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CC(=O)O)c1cccc(O)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 43.1 (3.4 g, 12 mmol) in 10:1 DMF/water (48 mL) was stirred overnight at 90° C. The mixture was cooled to room temperature, diluted with EtOAc, washed with 1 N HCl and brine, dried (MgSO4), and concentrated to afford 43.2 (2.4 g) as a pink oil. The crude product was used without further purification.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N-:36]=[N+:37]=[N-:38].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:31]([CH:33]3[CH2:35][CH2:34]3)=[N:38][N:37]=[N:36]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(COc2ccc(-n3nnnc3C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
Trifluoromethane sulfonic anhydride (9.42 ml) was added dropwise over 10 min to a solution of cyclopropanecarboxylic acid(4-benzyloxy-phenyl)-amide (15 g) and sodium azide (3.64 g) in acetonitrile (250 ml) at 0°. The reaction mixture was stirred at room temperature under nitrogen for 16 h. 10% Aqueous sodium hydrogen carbonate (80 ml) was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2×100 ml). The combined organic parts were dried over anhydrous sodium sulphate and concentrated in vacuo to give a brown oil. Purification by chromatography with ethyl acetate:isohexane (1:1) as eluant afforded the title compound (2.4 g) as a yellow solid, m.p. 118°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3([OH:34])[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:25][CH2:24]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: Cn1c(CN2CCC(C3(O)CCCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)CCCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 1-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)cyclopentanol were reacted to give 323. LCMS m/z: 531.3 (MH+)
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH2:17]([C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([CH3:27])[C:20]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH3:18].Cl.[CH3:34][CH2:35]N(C(C)C)C(C)C>C(O)C.C(O)(C)C>[CH2:34]([O:32][C:30](=[O:31])[CH2:29][CH2:28][C:20]1[C:21]([CH3:27])=[CH:22][C:23]([CH:25]=[CH:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:5]=23)=[O:10])=[CH:24][C:19]=1[CH2:17][CH3:18])[CH3:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(C=O)cc(C)c1CCC(=O)O
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)CCc1c(C)cc(C=CC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc1CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (143 mg, 0.606 mmol) and 3-(2-ethyl-4-formyl-6-methyl-phenyl)-propionic acid (200 mg, 0.908 mmol) in ethanol (15 mL) is treated with 5 N HCl in isopropanol (3 mL). The dark brown reaction mixture is stirred at rt for 3 h, then at 50° C. for 48 h before DIPEA (4 mL) is added. The solvent is removed in vacuo and the crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 10% to 95% acetonitrile) to give 3-{2-ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-6-methyl-phenyl}-propionic acid ethyl ester (157 mg) as a yellow oil; LC-MS: tR=1.27 min, [M+1]=467.43.
Reaction SMILES: [C:1]([NH:8][C:9](=O)[O-])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O:16]Cl)(C)(C)C.[CH2:18]1[C:22]2([CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:21]C=[CH:19]1>C(O)CC.[OH-].[Na+]>[CH3:7][C:4]([O:3][C:1]([NH:8][CH:9]1[CH:19]([OH:16])[CH2:18][C:22]2([CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:21]1)=[O:2])([CH3:5])[CH3:6]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC=CC2)CC1
Reactant: CC(C)(C)OC(=O)NC(=O)[O-]
Reactant: CC(C)(C)OCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: CC(C)(C)OC(=O)NC1CC2(CCN(C(=O)OCc3ccccc3)CC2)CC1O
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of Boc-carbamate (2.68 g, 22.9 mmol) in nPrOH (70 mL) at 25° C. was added an NaOH solution (32 mL, prepared from 900 mg of NaOH in 37 mL H2O) followed by tBuOCl (2.58 mL, 22.51 mmol). After 15 min, phenylmethyl 8-azaspiro[4.5]dec-2-ene-8-carboxylate (2 g, 7.4 mmol) in nPrOH (3 mL) was added followed by K2OsO2(OH)2 (109 mg, 0.295 mmol) dissolved in the remaining NaOH solution prepared above (5 mL). After 1 h, the solution was extracted with EtOAc, concentrated and purified via column chromatography (1-7% MeOH in DCM (1% NH4OH)) yielding the title compound (˜3.1 g, contaminated with residual Boc-carbamate) as a white solid: LCMS (ES) m/e 405 (M+H)+.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([I:9])[C:6]([F:10])=[CH:5][N:4]=1.[O:11]1CCOCC1>O>[F:10][C:6]1[C:7]([I:9])=[CH:8][C:3](=[O:11])[NH:4][CH:5]=1
Reactant: Fc1cc(I)c(F)cn1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 50 %

Procedure:
Concentrated HCl (50 mL) was added to a mixture of 2,5-difluoro-4-iodopyridine (2.0 g, 8.3 mmol) in 1,4-dioxane (350 mL) and water (100 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness and the residue was triturated in water (20 mL). The solids were collected via filtration and washed with water (2×30 mL) and hexanes (3×30 mL). The solid was dried under vacuum to afford the title compound as a yellow solid (1.0 g, 50%). MS (LCMS) m/z 240.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1H) 7.68 (d, J=2.34 Hz, 1H) 11.50 (br. s., 1H).
Reaction SMILES: ClC1C=CC(S(N(C2C=C(Cl)C=CC=2Cl)[C@H](C)CCN2CCSC2[C:20]([OH:22])=[O:21])(=O)=O)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[Cl:65])[C@H:43]([CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47][N:48]2[CH2:52][CH2:51][S:50][CH:49]2CC(O)=O)(=[O:41])=O)=[CH:35][CH:34]=1.[OH-:66].[K+]>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([N:42]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[Cl:65])[C@H:43]([CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47][N:48]2[CH2:52][CH2:51][S:50][CH:49]2[C:20]([OH:22])=[O:21])(=[O:41])=[O:66])=[CH:37][CH:38]=1
Reactant: [OH-]
Reactant: C[C@H](CCCCN1CCSC1CC(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](CCN1CCSC1C(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: ClCCl
Product: C[C@H](CCCCN1CCSC1C(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-(5-(2-carboxy-3-thiazolidinyl)-1(R)-methylpentyl)benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-(2,5-dichlorophenyl)-N-(5-(2-carboxymethyl-3-thiazolidinyl)-1(R)-methylpentyl)benzenesulfonamide with 50% aqueous KOH. Yield=67%; White foam: IR (neat, CH2Cl2) 1467, 1350, 1167, 1093, 753, 622 cm−1; MS (ESI+), 553 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:3]=1[NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:6]=1.[Sn](Cl)(Cl)(Cl)[Cl:29].[OH-].[Na+]>C(O)C>[ClH:29].[NH2:25][C:22]1[CH:23]=[CH:24][C:2]([CH3:1])=[C:3]([CH:21]=1)[NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[N:8]=[C:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:6]=1
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Product: Cl
Yield: 43.2 %

Procedure:
To a solution of 4-(2-methyl,5-nitroanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (75 mg, 0.200 mmol) in anhydrous ethanol (10 ml) was added slowly anhydrous tin chloride (152 mg, 0.800 mmol). The mixture was refluxed for 1 h and then rotary evaporated to leave a brown oil. The brown oil was basified with 2N NaOH to give a final pH of 8. The resulting precipitate was filtered and washed with ethyl acetate. The aqueous phase and organic phase was combined, washed with water (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate was rotary evaporated to dryness to give a dark yellow solid (33 mg, 44%). 1H NMR (CDCl3): 9.69-9.68 (m, 1H), 8.73-8.67 (m, 2H), 7.53 (s, 1H), 7.43-7.39 (m, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 6.64 (d, J=2.7 Hz, 1H), 6.61 (s, 1H), 3.01 (bs, 2H), 2.17 (s, 3H).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[OH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[ClH:20].[OH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:21]1[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: OC[C@@H]1CCCN1
Product: Cl
Product: OC[C@@H]1CCCN1CCOc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1

Procedure:
6-[2-((S)-2-hydroxymethylpyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 8% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 2-((S)-2-hydroxymethylpyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[Br:9][C:5]1[N:6]=[C:7]([NH:13][CH:10]2[CH2:12][CH2:11]2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NC1CC1
Product: Nc1ncc(Br)nc1NC1CC1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 2-amino-3,5-dibromopyrazine (1.00 g, 3.95 mmol) and cyclopropylamine (1.40 ml, 19.96 mmol). The reaction mixture was sealed under argon and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. Additional cyclopropylamine (1.0 mL) was added and the reaction was heated at 120° C. for 30 min in the microwave. Excess cyclopropylamine was removed in vacuo and the residue was dissolved in MeOH and evaporated onto silica gel and purified by flash chromatography (Isco (40 gram)) eluting with EtOAc:hexanes (0:1→1:2) to give 740 mg (82%) of a golden-brown tar. ESI MS 228.9 [M+1].
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:13]>[Mo](=O)(=O)=O.C1CCCCC1>[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:5][CH:1]2[CH2:4][CH2:20][CH2:15][CH2:16][CH2:3]2)[C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[N:18]([O:5][CH:1]2[CH2:4][CH2:11][CH2:10][CH2:9][CH2:3]2)[C:19]([CH3:22])([CH3:21])[CH2:20]1)=[O:13]
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 137.6 %

Procedure:
A two-phase mixture of 70% aqueous tert-butyl hydroperoxide (103.9 grams, 807 mmol), cyclohexane (200 ml) and sodium chloride (15 grams) is shaken in a separatory funnel. The organic phase is dried over anhydrous magnesium sulfate, filtered and added to 40 grms (101 mmol) of bis(2,2,6,6-tetramethylpiperidin-4-yl) succinate. Molybdenum trioxide (2.0 grams) is added and the mixture is heated at reflux for one hour. Water is collected in a Dean-Stark trap. The entire reaction mixture is then transferred to a Fischer-Porter pressure bottle and heated for six hours at 140° C. Additional tert-butyl hydroperoxide (90%, 10.1 grams, 101 mmol) is added and heating is resumed for another four hours. The colorless reaction mixture is filtered, concentrated and dissolved in heptane (200 ml). The heptane solution is passed through a column of silica gel with heptane as the eluent to obtrain 41.2 grams (69% yield) of bis(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl) succinate as a white solid melting at 122-126° C. Further elution of the column with 10:1 heptane:ethyl acetate affords the title compound as a mixture of cyclohexanediyl isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:11][C:10](=[O:12])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([N:4]1[CH2:3][C:2]([CH3:13])([CH3:1])[NH:11][C:10](=[O:12])[C:5]21[CH2:9][CH2:8][CH2:7][CH2:6]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CNC2(CCCC2)C(=O)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(Cc2ccccc2)C2(CCCC2)C(=O)N1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 6.72 g of 8,8-dimethyl-6,9-diaza-spiro[4.5]decan-10-one in 35 ml of DMF were added 4.8 ml of benzyl bromide and 6.9 ml of Hünig's base. The reaction was stirred at r.t overnight. The precipitated product was isolated by suction and washed with DMF and EtOAc. The filtrate was concentrated and the resulting residue was dissolved in EtOAc, washed with water, dried over Na2SO4, filtered and concentrated to yield a second fraction of the product. 9.62 g (96%) of the title compound were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.O[C:28]1[C:32]([CH:33]=[O:34])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:33]([C:32]1[C:28]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=4)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=3[CH3:14])=[CH:25][CH:26]=2)=[N:29][N:30]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=1)=[O:34]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CO)cc3)c(C)o2)c1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3)c(C)o2)c1
Reaction time: 15 h
Yield: 44.6 %

Procedure:
To a mixture of methyl 3-(4-{[4-(hydroxymethyl)phenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate (1.34 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), tributylphosphine (0.77 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.96 g) was added at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as crystals (0.62 g, yield 47%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.