Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:34][CH3:35])(=O)=O.CO>C1COCC1>[C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:34][CH3:35])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
60 mg (0.16 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (4 ml), and 0.18 ml (0.18 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) is added. Then 25 μl (0.199 mmol) of ethyl trifluoromethanesulfonate are added to the dark red solution. The decolorized solution is stirred for 10 min and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 35 mg (54% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:30]=[CH:29][C:13]2[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)(=[O:41])=[O:40])[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCNc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
6-[[1,2-Diphenyl-1H-benzimidazol-5-yl]amino]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11])=O.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[I-].[Na+]>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[I:11])=[CH:2][N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccccc1I
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2I)cnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.5 %

Procedure:
To a solution of 2-bromo-1-(2-iodophenyl)ethanone (2.70 g, 8.31 mmol) in anhydrous DMF (27 mL) was added Boc-guanidine (4.00 g, 24.9 mmol) and sodium iodide (2.47 g, 16.6 mmol). The reaction was stirred at ambient temperature for 72 hours upon which the mixture was partitioned between EtOAc (150 mL) and water (75 mL). The organic layer was successively washed with water (3×50 mL) and brine (2×50 mL) before being dried (Na2SO4) and evaporated to dryness. The resulting crude oil was purified via flash column chromatography (10-30% EtOAc/CH2Cl2) to obtain the target 2-amino-5-(2-iodophenyl)imidazole-1-carboxylic acid tert-butyl ester (1.84 g, 58%) as a tan foam: mp=121° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 1H), 7.27 (dd, 1H, J=1.6, 8.0 Hz), 7.49 (s, 1H), 7.41 (m, 1H), 7.00 (m, 1H), 6.59 (br s, 2H), 1.57 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 149.6, 148.8, 140.3, 137.4, 130.1, 128.8, 128.1, 108.6, 95.7, 85.0, 27.5; HRMS (ESI) calcd for C14H17IN3O2 (MH+) 386.0360. found 386.0359.
Reaction SMILES: [Cl-].C[N:3]([CH3:14])[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[N+:7](C)C.Cl.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26](C(N)=N)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:14]2[N:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[CH:6][N:7]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C=C(C=[N+](C)C)C(F)(F)F
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of (3-Dimethylamino-2-trifluoromethyl-allylidene)-dimethyl-ammonium chloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added 4-Benzyl-piperazine-1-carboxamidine hydrochloride ([7773-69-5], 0.66 g) and triethylamine (0.87 mL) and the reaction mixture was stirred for 3 hours at room temperature. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as a light yellow solid (0.79 g). MS (m/e): 323.4 (M+H+).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[NH:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>O>[C:22]([N:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:12]=[CH:11]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N=c1ccn(-c2ccccc2)nc1)c1ccccc1
Yield: 71.6 %

Procedure:
80 ml of toluene were added to a solution of 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 80 ml of water. First 6.8 g (48.4 millimoles) of benzoyl chloride and then, in the course of 15 minutes, 4.0 g (100 millimoles) of NaOH in 20 ml of water were added to the two-phase system at room temperature, whilst stirring, the mixture was stirred for a further hour at room temperature and the product was then filtered off under suction. The solid obtained was washed with water, dried and recrystallized from ethanol. 9.5 g (72% of theory) of 4-benzoylimino-1,4-dihydro-1-phenylpyridazine were isolated as yellow crystals of melting point 175°-176° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[N:3][C:4]=1[C:23]#[CH:24])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (2 g, 5.022 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (2.324 g, 5.148 mmol) were dissolved in MeCN (40.00 mL)/water (8.000 mL). K3PO4 (2.131 g, 10.04 mmol) was added and the mixture was degassed/flushed via nitrogen cycles (×5). Pd[P(tBu)3]2. (128.3 mg, 0.2511 mmol) was added and the reaction mixture placed under an atmosphere of nitrogen using vacuum/nitrogen cycles (×5). The reaction mixture was stirred at ambient temperature for 1 hour and then poured onto a stirred mixture of ethylacetate and saturated aqueous sodium metabisulphite at 10° C. The mixture was stirred for 5 minutes, shaken well and separated. The organic layer was washed with brine (×1), dried over MgSO4, filtered and the solution passed through a Florisil eluting with Ethylacetate. The filtrate was concentrated in vacuo and the residue purified by column chromatography (ISCO Companion, 330 g column, eluting with 0 to 40% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate as a beige solid (2.45 g, 76% Yield). H NMR (400.0 MHz, DMSO) δ 9.38 (s, 1H), 8.48 (d, 2H), 8.08 (d, 2H), 5.02 (s, 1H), 4.12-3.88 (m, 1H), 3.76 (br d, 1H), 3.43 (br s, 1H), 2.90-2.78 (m, 2H), 2.09 (br s, 1H), 1.75-1.61 (m, 2H) and 1.38-1.18 (m, 28H) ppm;
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([F:12])[CH:4]=1.CCN(C(C)C)C(C)C.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:12][C:5]1[CH:4]=[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:23]([CH3:22])[CH2:28]2)[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])c(F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
A solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (232 mg, 1 mmol) and Hunig's base (0.192 mL, 1.1 mmol) in DMF (3 mL) was treated with 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (200 mg, 1 mmol) in DMF (3 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated, re-dissolved in DCM and washed with water and brine, then dried and concentrated. The crude product was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as a colourless gum (327 mg). δH (CDCl3, 400 MHz) 8.03 (1H, m), 7.34 (1H, dd), 7.27 (1H, m), 4.22 (1H, br.s), 3.84 (1H, d), 3.58 (1H, d), 3.47 (1H, d), 3.13 (1H, td), 2.72 (1H, m), 2.54 (1H, m), 2.22 (1H, dd), 2.09 (1H, m), 1.46 (9H, s), 1.26 (3H, d) [δvalues corrected for incorrectly referenced TMS at 0.62 ppm on spectrum].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B#B>O1CCCC1>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: B#B
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(C)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 2,4-dimethylbenzoic acid (10 g; 66.6 mmol) in dry tetrahydrofuran (250 ml) was cooled to 0° C. and treated with a solution of diborane in tetrahydrofuran (135 ml of a 1.0M solution). The reaction mixture was stirred overnight before quenching with 1N HCl and extraction of the product into ethyl acetate. The organic phase was dried (MgSO4) and freed of solvent. The crude product was filtered through a plug of silica, eluting with 10% ethyl acetate in hexane, to obtain 8.62 g (95%) of the alcohol as a clear oil. 1H NMR (CDCl3): δ2.30, 2.32 (s, 6H total); 4.63 (d, 2H); 6.99 (m, 2H); 7.23 (d, 1H). IR (neat): 3338, 2921, 1504, 1453, 1378, 1240, 1039, 1005, 820 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]([OH:24])=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].CC1C=CC(S(O[C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][C@@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1Cl
Product: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 11 step (vii) using the product of step (iii) and the product of example 11 step (vi).
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[C:5]([O:7]C)=O.C[O-].[Na+].Br.[N:23]1([C:29]([NH2:31])=[NH:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CO>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:4]1[C:3]([OH:18])=[N:30][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:31][C:5]=1[OH:7]
Reactant: N=C(N)N1CCOCC1
Reactant: COC(=O)C(Oc1cccc(OC)c1)C(=O)OC
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Oc2c(O)nc(N3CCOCC3)nc2O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.7 %

Procedure:
To a solution of dimethyl-(3-methoxyphenoxy)-malonate (11.19 g) in methanol (100 ml) was added sodium methylate (6.48 g). The yellow solution was stirred for 6 h at rt. Then, morpholine-4-carboxamidine hydrobromide (8.40 g) was added and the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in water (150 ml) and extracted twice with diethyl ether (150 ml). The aqueous phase was acidified with 10% aq. citric acid. The solid that separated was collected, washed with water, evaporated twice from EA, and dried under high vacuum to give 5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4,6-diol (9.66 g) as a beige powder. LC-MS: tR=2.88 min, [M+1]+=320.19, [M−1]−=318.02.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]#[N:14])[C:11]#[N:12].Cl.S1C2C=CC=CC=2[NH:18]C1=C(C#N)C(=N)[O-].N>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]#[N:14])[C:11]([NH2:18])=[NH:12]
Reactant: N#CC(C#N)=C1Nc2ccccc2S1
Reactant: N#CC(C(=N)[O-])=C1Nc2ccccc2S1
Agent: Cl
Agent: N
Product: N#CC(C(=N)N)=C1Nc2ccccc2S1

Procedure:
In the first step, the benzothiazole 10 [L is a leaving group, as in Reaction Scheme 4] reacts with malononitrile in the presence of a strong base, such as sodium ethoxide in ethanol, to give the 2-[benzothiazol-2(3H)-ylidene]malononitrile 17. Reaction of this nitrile in suspension in a polar solvent with gaseous hydrogen chloride gives the 2-[benzothiazol-2(3H)-ylidene]-2-cyanoacetimidate 18, and reaction of the imidate with ammonia gives the corresponding 2-[benzothiazol-2(3H)-ylidene]-2-cyanoacetamidine 19. Compound 19 is then reacted with a β-diketone or equivalent, such as 2,4-pentanedione or ethyl 3-oxo-4,4,4-trifluorobutyrate, to form the pyrimidine ring [substituents not shown] of the compound of formula 6, in the presence of a base such as sodium ethoxide in an aprotic solvent under strong (e.g. microwave) heating. Finally, the compound of formula 6 is hydrolyzed to a compound of formula 8, as in Reaction Scheme 1. If the order is reversed, so that the hydrolysis is performed before the coupling, the hydrolysis proceeds as in Reaction Scheme 1, and the coupling may take place under milder conditions.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH2:20][CH:19]([N:21]([CH2:23][C@@H:24]2[C@@H:31]3[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]3)[C@H:26]([N:34]3[CH:42]=[N:41][C:40]4[C:35]3=[N:36][CH:37]=[N:38][C:39]=4[NH2:43])[O:25]2)[CH3:22])[CH2:18]1>CC(O)=O>[CH3:32][C:29]1([CH3:33])[O:30][C@@H:31]2[C@@H:24]([CH2:23][N:21]([CH3:22])[CH:19]3[CH2:18][CH:17]([CH2:16][CH2:15][C:14]4[NH:13][C:3]5[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=5[N:1]=4)[CH2:20]3)[O:25][C@@H:26]([N:34]3[CH:42]=[N:41][C:40]4[C:35]3=[N:36][CH:37]=[N:38][C:39]=4[NH2:43])[C@@H:27]2[O:28]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2ccc(OC(F)(F)F)cc2N)C1
Solvent: CC(=O)O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(OC(F)(F)F)ccc3[nH]2)C1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (1.0 g, 1.61 mmol) in HOAc (10 mL) was stirred at 65° C. overnight. The mixture was cooled to rt and concentrated. The residue was dissolved in DCM (50 mL), washed wth saturation NaHCO3 solution (10 mL×2), water (20 mL) and brine (30 mL). The residue was separated by chiral HPLC to afford the cis isomer (460 mg, yield: 47%) and the trans isomer (220 mg, yield: 23%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([NH:17][CH:18]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:29]([F:32])([F:31])[F:30])[CH:9]=2)[N:4]=1>O1CCOCC1>[NH:20]1[CH2:21][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:29]([F:31])([F:30])[F:32])[CH:9]=3)[N:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:12]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cc(C(F)(F)F)nc3ccc(C(F)(F)F)cc23)C1
Solvent: C1COCCO1
Product: O=C(CNc1cc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12)NC1CNC1

Procedure:
A solution of tert-butyl 3-(2-((2,6-bis(trifluoromethyl)quinolin-4-yl)amino)acetamido)azetidine-1-carboxylate (291 mg, 1.04 mmol) in dry dioxane (5 mL), prepared in Step C above, was de-protected as described in example to afford the product. ESI-MS (m/z): Calcd. For C16H14F3N4O: 392.11. found: 393 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:39][CH3:40]
Reactant: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1O

Procedure:
0.6 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 6 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 190° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[CH3:12][O:13]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:11][C:4]1[C:3]([O:2][CH3:1])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[CH:12]=[O:13]
Reactant: COc1cccc(OC)c1Cl
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c(OC)c1Cl

Procedure:
2-chlororesorcinol dimethyl ether (3.4 g) is dissolved in 20 ml of CH2Cl2 and TiCl4 (4.3 ml) is added. To this solution is added dichloromethyl methyl ether (2.3 g). After 30 minutes the reaction mixture is poured into H2O into H2O and extracted with ether. Drying and evaporation gives 3-chloro-2,4-dimethoxybenzaldehyde, mp 107°-108° C.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([P:10]([OH:14])([O:12][CH3:13])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH-].[Na+].[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:19]1([CH2:25][C:26]([NH:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([P:10]([OH:14])([O:12][CH3:13])=[O:11])[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COP(=O)(O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COP(=O)(O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred slurry of 532 mg. (0.002 mole) of 6-amino-2,2-dimethyl-3-(O-methylphosphono)penam in 10 ml. of water is cooled to 0° C., and the pH is then adjusted to 8.0 using 1N sodium hydroxide. To this solution is then added 0.27 ml. (310 mg., 0.002 mole) of phenylacetyl chloride, in portions, with the pH of the solution being maintained between 7 and 8 during the addition, using 0.1 N sodium hydroxide. The solution is stirred in additional 30 minutes at 0° C. and pH 7. It is concentrated in vacuo to a small volume and the title compound purified by Sephadex LH-20 chromatography, eluting with water.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][O:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[C:39](=O)[C:38]=2[CH:49]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][O:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3/[C:39](=[CH:7]\[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:38]=2[CH:49]=1
Reactant: O=C1c2cc(Br)ccc2COc2ccccc21
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC/C=C1/c2cc(Br)ccc2COc2ccccc21

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (31 g., 60.9 mmole), 122 mmole of n-butyl lithium in hexane, and 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (12.7 g., 43.8 mmole) were reacted in 750 mL dry tetrahydrofuran by the procedure of Example I, Step b. This provided an E/Z (1:6) isomeric mixture of bromoamines. Recrystallization of the mixture from ethyl acetate/methanol gave 1.2 g. of pure Z-isomer as its hydrochloride salt, melting range 91°-100° C. and 2.16 g. of an E/Z (1:4) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) δ: 6.94-7.46 (m, 7H, aromatic), 5.64 (t, J=8.0 Hz, 1H, CH=), 5.15 (br s, 2H, CH2O), 3.07 (m, 4H, NCH2CH2), 2.75 (s, 6H, NMe2).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:11]([Mg]Br)([CH3:13])[CH3:12]>>[Br:8][C:6]1[CH:7]=[C:2]([CH:11]([CH3:13])[CH3:12])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)[Mg]Br
Product: CC(C)c1cc(Br)cn(C)c1=O

Procedure:
Examples 512-514 as described in Table 23 were prepared in three steps. Using conditions similar to those described by Malhotra, et. al. in Organic Letters 2013, Vol. 15, No. 14, pp. 3698-3701 (supporting information, compounds 4c and 3a), 3,5-dibromo-1-methylpyridin-2-one was alkylated at the 3-position using isopropylmagnesium bromide to give 5-bromo-1-methyl-3-propan-2-ylpyridin-2-one which was then reacted with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, 1-methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of the example shown under Synthetic Method in Table 23 and reacted in the same way as the example to obtain the title compounds.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[Cl:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:11]=[C:10]2[N:20]([CH2:29][CH2:30]I)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]=12>C(Cl)Cl>[Cl:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[C:10]2[N:20]([CH2:29][CH2:30][N:1]3[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]3)[N:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:9]=12
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Reactant: O[C@@H]1CCNC1
Solvent: ClCCl
Product: O[C@@H]1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A solution of (R)-3-pyrrolidinol (166 mg, 1.9 mmol) in CH2Cl2 (1.5 ml) was added to 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (example 74 step 1) (113 mg, 0.24 mmol) and the reaction stirred at ambient for 24 h. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC to give Compound 83 as an orange solid (17 mg).