Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:15])[CH:3]=[CH:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.O1CCOCC1>[OH:15][C:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:1]([OH:16])=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(O)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 832.4 %

Procedure:
To 2.00 g (1.00 mmol) of 1,4-anthracenedione, a solution of 6.68 g (38.0 mmol) of sodium hydrosulfite in 50 mL of water and 50 mL of 1,4-dioxane was added. The resulting mixture was stirred at 25° C. for 3 h, and added 100 mL of water. The mixture was cooled over an ice-water bath, and the precipitated dark green solids were collected by filtration, washed twice with water, and dried under vacuum to give 1.75 g (87% yield) of 1,4-dihydroxyanthracene, mp 167-169° C.; 1H NMR d 8.70 (s, 2H, C 9,10 Hs), 8.05 (m, 2H, C 5,8 Hs), 7.50 (s, 2H, C 6,7 Hs), 6.60 (s, 2H, C 2,3 Hs).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6](Cl)[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3].O.[NH2:28][NH2:29]>C(O)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:28][NH2:29])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(Cl)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
51.7 g of 6-n-propyl-2-methyl-4-chloro-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 10, are dissolved in 150 ml of ethanol and 90 ml of hydrazine hydrate. The mixture is heated to reflux for 6 hours and the solvent is concentrated to one half under vacuum and then treated with water. The crystals formed are drained, washed with water and then with ether and dried to give 46 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:9]1[C:10]([CH:12]([CH3:14])[CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1cc(C(C)C)ccc1C(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.C(#N)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[O:16]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(Br)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (6.87 g, 48 mmol), 3-bromo-4-fluorobenzaldehyde (8.12 g, 40 mmol), and potassium carbonate (6.63 g, 48 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12 mL) and acetonitrile (8 mL) was heated at 80° C. under N2 atmosphere for one day. Reaction mixture was cooled down to room temperature and poured onto water (150 mL). The mixture was extracted with methylene chloride. The organic layer was dried (MgSO4) and concentrated to give the title compound as an off-white solid (12.4 g, 96%); mp 63–64° C.; 1H NMR (300 MHz, CDCl3) δ 1.93 (t, J=5.7 Hz, 4H), 3.25 (t, J=5.4 Hz, 4H); 4.02 (s, 4H), 7.12 (d, J=4.2 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 9.84 (s, 1H); MS (ES) m/z: 325.7 (MH+); HRMS Calcd. for C14H16BrNO3 (MH+): 325.0314. Found: 325.0288.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[NH:6][C:5]1=O.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>CN(C)C=O>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29]/[CH:3]=[C:4]3\[CH2:5][N:6]=[CH:7][C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\CN=Cc4ccccc43)cc2)CC1
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (95.6 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 163 mg (90%) of yellow solid mp 245-246° C.; MS (ESI) m/z 363.19 (M+1); Analysis for C21H22N4O2: Calcd: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.49; H, 6.10; N, 15.36.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[O:21]([CH2:20][CH2:19][O:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCOc1ccccc1
Reactant: Oc1cc2ccccc2cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc2ccccc2cc1OCCOc1ccccc1
Temperature: 135 °C
Yield: 40 %

Procedure:
A mixture of 2,3-dihydroxynaphthalene (5.6 g) and sodium bicarbonate powder (2.9 g) in dimethylformamide (50 mL) was stirred and heated at 135° C. for 1 hour. When the gas evolution ceased, the mixture was cooled to about 60° C. and beta-bromophenetole (7 g) was added. The mixture was stirred at 60° C. overnight, cooled, diluted with water and filtered. The solids were crystallized from dichloromethane-diethyl ether to give 3.9 g of 3-(2-phenoxyethoxy)-2-naphthol as a colorless solid, mp 141°-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[N:31]=[C:30]([CH2:32][OH:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:15]1([NH:14][C:12](=[O:13])[C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([CH2:32][OH:33])[N:31]=4)=[CH:23][CH:22]=3)[CH:10]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: OCc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CO)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
3 -{[4-(hydroxy)benzoyl]amino }-N-cyclopropyl-4-methylbenzamide (100 mg, 0.323 mmol), [6-(bromomethyl)pyridin-2-yl]methanol (71 mg, 0.355 mmol) and potassium carbonate (49 mg, 0.355 mmol) were mixed in acetonitrile (3 mL) and the reaction was stirred at room temperature for 16 h. The reaction was then heated at 100° C. in the microwave for 10 mins. Water (10 mL) was added and the mixture was extracted with DCM (3×15 mL). The organic layers were combined and evaporated to give a white solid which was triturated with DCM to give the title compound as a white solid (80 mg, 58%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.6S (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 4.59 (s, 2H), 5.24 (s, 2H), 7.16 (d, 2H), 7.32 (d, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (d, 2H), 8.36 (d, 1H), 9.82 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].CCN(CC)CC.Br[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH2:32][CH3:33])[CH:26]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([NH:4]/[C:5](=[CH:16]/[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH2:32][CH3:33])[CH:26]=1)/[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCc1cc(Br)ccc1N
Reactant: C=C(NC(C)=O)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(/C=C(/NC(C)=O)C(=O)OCc2ccccc2)ccc1N
Yield: 25.7 %

Procedure:
To benzyl 2-(acetylamino)acrylate (80.0 mmol) in acetonitrile (200 mL) was added Pd(OAc)2 (488 mg, 2.18 mmol), (o-Tol)3P (1.32 g, 4.35 mmol), Et3N (20 mL) followed by addition of 4-bromo-2-ethylaniline (14.5 g, 72.5 mmol). The reaction mixture was heated to reflux overnight, concentrated under reduce pressure, taken up in ethyl acetate, washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was precipitated from ethyl acetate/hexane to provide the titled compound (6.3 g). The filtrate was precipitated a second time to provide and additional 5 g of the titled compound. MS (ESI(+)) m/e 339 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.40-7.20 (m, 8H), 6.59 (d, 1H), 5.52 (s, 2H), 5.16 (s, 2H), 2.42 (q, 2H), 1.98 (s, 3H), 1.13 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=1[CH3:40])([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:35][C:34]=1[CH3:40])([CH3:30])[CH3:31])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 134 mg (0.56 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 257 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy-2-methyl-propionic acid ethyl ester could be isolated.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC([NH:42][C@H:43]([C:50]([OH:52])=O)[CH2:44][N:45]1[CH:49]=[CH:48][CH:47]=[N:46]1)=O)C1C=CC=CC=1.[NH2:53][C@@H:54]([CH2:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C@@H:55]([OH:61])[C@H:56]([CH:58]1[CH2:60][CH2:59]1)[OH:57]>C(#N)C>[NH2:42][C@@H:43]([CH2:44][N:45]1[CH:49]=[CH:48][CH:47]=[N:46]1)[C:50]([NH:53][C@@H:54]([CH2:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C@@H:55]([OH:61])[C@H:56]([CH:58]1[CH2:60][CH2:59]1)[OH:57])=[O:52]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cn1cccn1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@@H](Cn1cccn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h

Procedure:
1.03 g (2.83 mmol) of HBTU and 0.39 ml (2.83 mmol) of triethylamine were added to a solution of 820 mg (2.83 mmol) of N-[(benzyloxy)carbonyl]-3-(pyrazol-1-yl)-L-alanine [J. Am. Chem. Soc. 107, 7105 (1985)]and 644 mg (2.83 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol in 28 ml of acetonitrile and the mixture was stirred at room temperature overnight. The crystals obtained after filtration were dissolved in 30 ml of ethanol and hydrogenated at 400 for two hours. Filtration over diatomaceous earth and evaporation under reduced pressure yielded 670 mg of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyrazol-1-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18]C(=O)OC(C)(C)C)[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C@@H:3]([C@H:4]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[CH3:7])[CH2:2][OH:1]
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CO
Reaction time: 1 h

Procedure:
Tert-butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (0.10 g, 0.28 mmol) was taken up in 3 mL of DCM. 1 mL of TFA was added. The mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was taken up in 5 mL of DCM and 5 mL of 5% aq NaOH. The mixture was partitioned, and the aqueous portion was extracted three times with 5 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded (2S,3S,E)-2-amino-3-(4-(trifluoromethyl)phenyl)hex-4-en-1-ol, which was used without any further purification.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][S:6][C:5]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:4]=2[C:3]1=[O:15].[BH4-].[Na+].Cl>CO.O>[Br:1][CH:2]1[CH2:7][S:6][C:5]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:4]=2[CH:3]1[OH:15]
Reactant: NS(=O)(=O)c1cc2c(s1)SCC(Br)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1cc2c(s1)SCC(Br)C2O
Temperature: -10 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A suspension of 5,6-dihydro-5-bromo-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (2.58 g, 0.0079 m) in methanol (100 ml) was cooled to -10° C. and vigorously stirred while a solution of sodium borohydride (0.45 g, 0.012 m) in water (10 ml) was added over 25 minutes while maintaining the temperature at -10° to -5° C. The mixture was stirred at ambient temperature for 2 hours, then acidified with 6N hydrochloric acid and concentrated in vacuo below 40° C. The residue was distributed between ethyl acetate (100 ml) and water (100 ml), the aqueous layer was separated and again extracted with ethyl acetate (2×75 ml). The combined extracts were washed with water, dried over sodium sulfate and concentrated in vacuo to give 2.42 g (93%) of crude product. Partial purification was effected by chromatography on silica gel, eluting with 5% methanol-chloroform, to yield 1.71 g of product which was used in the subsequent step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:19][C:18]=2[C:37]2[N:45]=[C:44]([CH3:46])[N:43]=[C:42]3[C:38]=2[N:39]=[CH:40][N:41]3C2CCCCO2)=[CH:12][CH:11]=1.C(Cl)Cl>>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]([C:37]3[N:45]=[C:44]([CH3:46])[N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:21][N:22]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (3.00 mL, 38.9 mmol) was added to a stirred mixture of tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (155 mg, 0.252 mmol) in DCM (3 mL, 46.6 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and then diluted with DCM, NaHCO3 (aq) and water (10 mL each). The separated aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(piperazin-1-ylmethyl)pyridin-2-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[F:18][C:19]([F:34])([F:33])[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([OH:32])=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[O:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:32][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([C:19]([F:34])([F:33])[F:18])=[N:21][O:22][C:23]=2[C:28]=1[CH2:29][CH2:30][CH3:31]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: COC(=O)Cc1ccc(OCCCBr)c(F)c1
Product: CCCc1c(OCCCOc2ccc(CC(=O)OC)cc2F)ccc2c(C(F)(F)F)noc12

Procedure:
Using the method in example 17 step D substituting methyl 3-fluoro-4-(3-bromopropyloxy)phenylacetate and 3-trifluoromethyl-7-propyl-6-hydroxybez-[4,5]-isoxazole as the starting materials, the titled compound was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][CH:16]=1>>[NH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([NH:14][C:2]3[N:7]=[C:6]([NH:14][C:15]4[CH:23]=[C:22]5[C:18]([CH:19]=[N:20][NH:21]5)=[CH:17][CH:16]=4)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=3)[CH:23]=2)[CH:19]=[N:20]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Product: CCOC(=O)c1cnc(Nc2ccc3cn[nH]c3c2)nc1Nc1ccc2cn[nH]c2c1

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-aminoindazole were reacted to yield N2,N4-bis(6-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.76 (s, 1H), 7.73(d, 2H J=8.8), 7.54 (m, 4H), 7.36 (d, 2H, J=9.5 Hz), 4.3 (q, 2H, J=7.0 Hz), 1.34 (3H, J=7 Hz); LCMS: ret. time 27.59 min.; purity: 95%; MS (m/e): 415 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 5-bromo-3-pyridineacetic acid (500 mg, 2.314 mmol) in DMF (3 mL) is added TBTU (1.11 g, 3.472 mmol). Morpholine (0.61 mL, 6.94 mmol) is added dropwise and the mixture is stirred at room temperature for 18 h. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-4.5% MeOH in DCM as the gradient to afford 2-(5-bromo-pyridin-3-yl)-1-morpholin-4-yl-ethanone.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:18]([C:17]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:21])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cccc(-c2csc(N)c2C#N)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2scc(-c3cccc(OC)c3)c2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A mixture of 2-amino-4-[3-(methyloxy)phenyl]-3-thiophenecarbonitrile (1 g, 4.34 mmol) (Description 13), ethyl acetoacetate (0.550 mL, 4.34 mmol) and SnCl4 (1.019 mL, 8.68 mmol) in toluene (25 mL) was stirred at RT for 30 min followed by reflux for 3 h. After cooling to RT, the mixture was quenched with 2M NaOH (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organics were washed with brine (50 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (915 mg). LCMS (A) m/z: 343 [M+1]+, Rt 1.25 min (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.C[O-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]#[N:26]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[C:25]#[N:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(CS)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc(C(F)(F)F)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of p-methoxybenzylmercaptan (20.0 g, 0.13 mol) and sodium methoxide (7.0 g) in N,N-dimethylformamide (55 ml) was added dropwise with stirring under a nitrogen atmosphere to a solution of 4-chloro-3-cyanobenzotrifluoride (26.7 g, 0.13 mol) in N,N-dimethylformamide (35 ml) cooled in an ice bath. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice-water and extracted several times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and evaporated to afford in essentially quantitative yield, 2-(4'-methoxybenzylthio)-5-trifluoromethylbenzonitrile as an oil; 60 MHZ NMR spectrum in chloroform-d was in accord with the desired structure. A mixture of the crude product in ethanol (110 ml) and 20% aqueous sodium hydroxide (450 ml) was heated at reflux temperature with stirring for 24 hours. The cooled hydrolysis mixture was concentrated, the resulting solid filtered, and washed with ether. The mother liquors were partitioned and the ethereal layer evaporated. The filtered solid was dissolved in methanol and added to the residue from the mother liquor work-up. The solution was evaporated, the resulting oil suspended in water and the aqueous mixture acidified with 6N hydrochloric acid. The precipitated solid was filtered and dried in vacuo over phosphorous pentoxide; yield 41 g (92%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[Se:20][C:3]=1[C:4]=23.Br.Br[CH2:27][CH2:28][NH2:29].Br>C(O)C>[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:27][CH2:28][NH2:29])=[C:3]3[Se:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: NCCBr
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)[Se]c1ccccc1-2
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)[Se]c1ccccc1-2
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 3.7 g (0.01 mole) of 5-amino-N,N-diethyl-2H[1]benzoselenino[4,3,2-cd]indazole-2-ethanamine, 5.9 g (0.029 mole) of 2-bromoethylamine, hydrobromide, and 25 ml of ethanol is heated under reflux for ten hours. Additional 2-bromoethylamine, hydrobromide (2.0 g) is added and the solution is heated at reflux for 38 hours, then allowed to cool to 25° C. The solids are collected and washed with cold ethanol to give 3.5 g of the dried product as a salt with 2.8 equivalents of hydrogen bromide; mp 268°-270° C. (dec.).