Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.[CH:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](Cl)=[O:39])=[CH:32][CH:31]=1>CN(C)C=O>[C:33]1([CH2:36][CH2:37][C:38]([N:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]3[C:12]4=[C:13]5[S:19][CH:18]=[CH:17][C:14]5=[N:15][CH:16]=[C:11]4[N:10]=[C:9]3[CH:20]([OH:22])[CH3:21])[CH2:3]2)=[O:39])[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.044 mmol) (Example 50, step 4) and triethylamine (24.7 μL, 0.177 mmol) in N,N-dimethylformamide (0.3 mL) was added benzenepropanoyl chloride (8.6 μL, 0.058 mmol). The resulting mixture was stirred for 90 min at room temperature. The mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.5 mg (34%) of the desired product. LCMS calculated for C24H27N4O2S (M+H)+: m/z=435.2. Found: 435.1. 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 7.71-7.66 (m, 1H), 7.65-7.57 (m, 1H), 7.34-7.27 (m, 2H), 7.26-7.16 (m, 2H), 7.12 (d, J=6.9 Hz, 1H), 5.21 (s, 1H), 4.83 (d, J=13.1 Hz, 2H), 4.78-4.64 (m, 1H), 4.04-3.87 (m, 1H), 3.61-3.23 (m, 3H), 3.04-2.85 (m, 2H), 2.77-2.60 (m, 2H), 2.15 (s, 1H), 1.97 (d, J=14.4 Hz, 1H), 1.81 (d, J=6.5 Hz, 2H), 1.50 (d, J=13.1 Hz, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][C:11]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1>C(Cl)Cl>[F:40][C:9]([F:8])([F:41])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:12][C:11]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([F:38])([F:39])[F:37])[CH2:32][CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1
Reactant: Cn1c(Nc2cc(CN)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: CC(C)(C)S(=O)Cl
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 99, step (a) using 2-methylpropane-2-sulfinic chloride (117 mg, 0.83 mmol), 4-trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (400 mg, 0.79 mmol), TEA (160 mg, 1.58 mmol) and DCM (5 mL).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: NN
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Under ice-cooling, 8.42 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 3.0 g of hydrazine monohydrate and 60 ml of tetrahydrofuran were mixed, and the mixture was stirred at room temperature for 3 hours. A deposited precipitate was collected by filtration, and washed successively with tetrahydrofuran and methyl t-butyl ether to obtain 4.85 g of 3-bromo-N-[4,6-dibromo-2-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.C[C:12]1[CH:17]=[C:16](C)[CH:15]=[CH:14]C=1Br.[Mg].C1(=O)CCCC1.OS(O)(=O)=O>CCOCC.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:14]1[CH2:15][CH2:16][CH2:17][CH:12]=1
Reactant: Cc1ccc([Mg]Br)c(C)c1
Reactant: Cc1ccc(Br)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: O=C1CCCC1
Solvent: CCOCC
Product: Cc1ccc(C2=CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To a 5° C. solution of 2,4-dimethylphenylmagnesium bromide (prepared from 18.5 g (100 mmol) of 2,4-dimethylbromobenzene and 2.5 g (105 mmol) of magnesium turnings) in 100 mL of ether, was added cyclopentanone (8.4 g, 100 mmol) in 25 mL of ether. The mixture was stirred at room temperature for 1 hour and was then heated under reflux for 0.5 hours. The solution was cooled in an ice bath, 60 mL of 30% aqueous H2SO4 was carefully added, and the resulting mixture was heated under reflux for 2 hours. Water was added and the mixture was extracted with ether. The ether extract was washed with aqueous sodium bisulfite solution, aqueous sodium bicarbonate, and brine, dried, and evaporated. Purification of the residue by flash chromatography (hexane) afforded 6 g of 1-(2,4-dimethyl-phenyl)cyclopentene.
Reaction SMILES: C(O)C.[CH:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:6])[CH3:5].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(N(CC)CC)C>[CH2:18]([O:17][C:15]([CH2:14][N:10]1[CH2:11][CH2:12][N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9]1)=[O:16])[CH3:19]
Reactant: CC(C)N1CCNCC1
Reactant: CCOC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(C)C)CC1
Yield: 68.3 %

Procedure:
One hundred milliliters of an ethanol solution containing 7 g of 1-isopropylpiperazine, 6.2 g of ethyl chloroacetate and 9.2 m of triethylamine was heated and refluxed for 4 hours. After being concentrated under reduced pressure, the resulting mixture was added with ethyl acetate. Insoluble matter was removed by filtration. Thereafter, the residue was purified by silica gel chromatography (eluent: a 20:1 mixture of chloroform and methanol) to obtain 7.4 g of 1-ethoxycarbonylmethyl-4-isopropylpiperazine as a light brownish oily substance.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[Li].C[Si]([NH-])(C)C.[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1>[CH2:1]([C@H:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:24][CH:23]=[CH2:22])[C:11]([O:13][CH3:14])=[O:12])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CCN(CC(=O)OC)C1=O
Reactant: C=CCBr
Agent: C[Si](C)(C)[NH-]
Agent: [Li]
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC)N1CC[C@H](CCCC)C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
Step B (4): (S)-Methyl 2-(3-butyl-2-oxopyrrolidin-1-yl)acetate (0.5 g, 2.35 mmol) from step B (3) was dissolved in dry THF (30 mL) and cooled to −78° C. Lithium bis(trimethylsilylamide (1.0M in THF, 2.70 mL, 2.70 mmol, Aldrich) was added while the temperature was maintained below −60° C. The mixture was cooled to −78° C. and stirred for 15 min. A solution of allyl bromide (0.24 mL, 2.72 mmol, Aldrich) in 10 mL of THF was added dropwise and the resulting mixture was stirred for 48 h. The reaction was quenched with acetic acid (0.5 mL) and poured into 75 mL of 0.5 M H2SO4. The aqueous layer was extracted with EtOAc and the organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography (5-35% EtOAc/hexanes linear gradient) to give 170 mg (29% yield) of (s)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (diastereomer A, first to elute) as a colorless oil and 130 mg of (R)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (diastereomer B, second to elute) as a colorless oil. Data for diastereomer A: LC-MS (M+H)+=254.3; 1H NMR (500 MHz, CDCl3) δ 5.47-5.95 (m, 1H), 4.98-5.20 (m, 2H), 4.87 (dd, J=10.99, 4.88 Hz, 1H), 3.69 (s, 3H), 3.32-3.51 (m, 1H), 3.15-3.34 (m, 1H), 2.60-2.80 (m, 1H), 2.41-2.53 (m, 1H), 2.26-2.40 (m, 1H), 2.05-2.23 (m, 1H), 1.76-1.94 (m, 1H), 1.61-1.77 (m, 1H), 1.18-1.47 (m, 5H), 0.78-0.97 (m, 3H). Data for diastereomer B: LC-MS (M+H)+=254.36; 1H NMR (500 MHz, CDCl3) δ 5.57-5.78 (m, 1H), 4.99-5.18 (m, 2H), 4.88 (dd, J=10.99, 4.88 Hz, 1H), 3.69 (s, 3H), 3.32-3.48 (m, 1H), 3.21-3.32 (m, 1H), 2.64-2.79 (m, 1H), 2.34-2.53 (m, 2H), 2.10-2.30 (m, 1H), 1.74-1.91 (m, 1H), 1.46-1.74 (m, 1H), 1.20-1.40 (m, 5H), 0.78-1.00 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Oc1cccnc1Cl
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccnc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-3-pyridinol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 213.4-216.2 ° C. 1H NMR (acetone-d6/300 MHz) 8.33 (m, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.64 (m, 1H), 7.53 (m, 1H), 6.67 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). ESHRMS m/z 405.9890 (M+H, Calc'd 405.9861). Anal. Calc'd for C16H8Cl2F3NO4: C, 47.32; H, 1.99; N, 3.45; Cl, 17.46. Found: C, 47.36; H, 1.98; N, 3.40; Cl, 17.14.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH2:21]([O:23][C:24]([CH2:26][C:27](Cl)=[O:28])=[O:25])[CH3:22].Cl.[Na]>CN(C)C=O>[CH2:21]([O:23][C:24]([CH2:26][C:27]([NH:1][C:2]1[S:3][C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1)=[O:28])=[O:25])[CH3:22]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(-c2nc(N)sc2-c2cccnc2)cc1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In 5 ml of dimethylformamide was dissolved 1 g of 2-amino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. To the solution was added under ice-cooling 580 mg of ethoxycarbonylacetylchloride. The mixture was stirred for 30 minutes, to which was then added a saturated aqueous solution of sodium hydrogen chloride. The resultant was subjected to extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated, followed by recrystallization from tetrahydrofuran to give 850 mg (61%) of 2-ethoxycarbonylacetylamino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 202°-203° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCC(c1ccccc1)c1ccccc1
Product: CC(C)(C)N1C(=O)C(NCC(c2ccccc2)c2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2,2-diphenylethanamine in a similar manner as described for Example 1. 1H NMR (500 MHz CDCl3): δ 7.59-7.54 (m, 2H), 7.48-7.43 (m, 3H), 7.27 (t, 4H), 7.22 (t, 2H), 6.97 (d, 4H), 5.25 (t, 1H), 3.96 (t, 1H), 3.50 (dd, 2H), 1.70 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.6, 140.8, 135.0, 131.7, 129.9, 129.0, 128.0, 127.3, 125.3, 108.1, 61.7, 50.7, 48.3, 27.8; Mass Spectrum: M+H+ 461.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH3:20][C:21]([Mg]Br)=[CH2:22]>C1COCC1>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[C:21]([CH3:22])=[CH2:20])[N:3]=[CH:2]1
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(O)(c1ccc2cc(OC)ccc2c1)c1c[nH]cn1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.80 g) with 2-propen-2-ylmagnesium bromide in THF (1.0 M, 9.5 ml) was carried out to give the titled compound (0.76 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([NH:16][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])c(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a cooled (5° C.) solution of 4-chloro-3,5-dinitrobenzonitril (50 g, 0.22 mol) in anhydrous DMF (200 ml) was added aniline (40 ml, 0.44 mol) dropwise over 1 hour. The resultant mixture was stirred for additionally 1 hour at 0° C. and then poured into ice-water (1400 g). The precipitate was filtered off, washed with water and air-dried to afford N-phenyl-4-cyano-2,6-dinitroaniline, quantitatively.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][C:15](N)=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:20])=[N:13]3)[CH2:4][CH2:3]1.Cl.N([O-])=O.[Na+].[PH2](O)=O.[OH-].[Na+]>C(O)CCCCCCC.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:20])=[N:13]3)[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(N3CCC(O)CC3)c(F)cc(N)c2n1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: CCCCCCCCO
Solvent: O
Product: Cc1ccc2c(N3CCC(O)CC3)c(F)ccc2n1
Reaction time: 7 h
Yield: 47.9 %

Procedure:
To 1.5 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-8-amino-quinaldine were added 10 ml of concentrated hydrochloric acid and 3 ml of water, and 2 ml of an aqueous solution of 0.39 g of sodium nitrite was added dropwise to the mixture at -2° C. After 3 minutes one drop of n-octanol (defoaming agent) was added to the mixture. Then, 5.7 g of hypophosphorous acid (50% aqueous solution) already cooled to 0° C. was added dropwise to the mixture at -2° C. Thereafter, stirring was continued at 0°-5° C. for 7 hours. The reaction mixture was poured into water, rendered alkaline with an aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was dried over sodium sulfate and the solvent was distilled off to give 0.68 g of 5-(4-hydroxy-1-piperidyl)-6-fluoroquinaldine.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:13](=[O:21])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([NH:22][C@H:12]([C:13](=[O:21])[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:33])=[O:5])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 5 h
Yield: 120.2 %

Procedure:
To a solution of ester 51 (76 mg, 0.167 mmol) in CH2Cl2 (5 mL) was added TFA (0.5 mL) and the reaction solution stirred for 5 h. The solution was concentrated under reduced pressure to give crude 52 as a white solid (80 mg) which was used in the next step without purification. TLC Rf 0.32 (5% MeOH/CH2Cl2); 1H-NMR (400 MHz, DMSO-d6) δ 11.93 (br s, 1H), 9.99 (s, 1H), 7.58 (d, 2H), 7.55 (d, 1H), 7.35 (m, 4H), 7.29 (t, 2H), 7.03 (t, 1H), 5.02 (m, 2H), 4.11 (br dd, 1H), 2.17 (t, 2H), 1.59 (m, 2H), 1.48 (m, 2H), 1.22 (m, 4H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19].O>CS(C)=O>[CH2:16]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/Cn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
This example illustrates a synthesis of 1-(3,7-Dimethyl-2,3,6,7-dioxidoctyl)-3,7-dimethylxanthine (inventive compound no. 2552). Sodium hydride (95%) (0.28 g, 12 mmol) was added to a solution of theobromine (2.16 g, 12 mmol) in dimethylsulfoxide (50 mL). After 20 minutes of stirring, geranyl bromide (2.17 g, 10 mmol) was added. After 6 hours of stirring at room temperature, the reaction mixture was warmed to 60° C. for 3 hours and then poured into a separatory funnel containing 150 mL of water and extracted with dichloromethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% acetone/petroleum ether eluant to yield 2.1 g (66.5% yield) 1-(Geranyl)-3,7-dimethylxanthine (inventive compound no. 2545).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:35])[CH2:11][NH:12][S:13]([NH:16][C:17]([N:19]2[CH2:22][C@H:21]([NH:23]C(=O)OCC3C=CC=CC=3)[C:20]2=[O:34])=[O:18])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].CCOCC>C1(SC)C=CC=CC=1>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:23][C@H:21]1[CH2:22][N:19]([C:17]([NH:16][S:13]([NH:12][CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)=[O:35])(=[O:15])=[O:14])=[O:18])[C:20]1=[O:34]
Reactant: O=C(CNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)Nc1ccc(O)c(O)c1
Solvent: CSc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NCC(=O)Nc2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.4 g (2.76 mmol) of (S)-[1[[[[[2-[(3,4-dihydroxyphenyl)amino]-2-oxoethyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester in 1.1 g of thioanisole was added 3 ml of trifluoroacetic acid and the mixture was stirred overnight at room temperature. 50 ml of ether was added and the resulting crystals were filtered off, washed twice with ether and finally triturated with dichloromethane; yield: 1.22 g.
Reaction SMILES: Cl.[NH:2]=[C:3]1[S:6][CH2:5][S:4]1.Cl[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C([O-])(=O)C.[Na+]>C1C=CC=CC=1>[CH:11]([O:10][C:8]([N:2]=[C:3]1[S:6][CH2:5][S:4]1)=[O:9])([CH3:13])[CH3:12]
Reactant: N=C1SCS1
Reactant: CC(C)OC(=O)Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)OC(=O)N=C1SCS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a well-stirred mixture of 2.8 g. of 2-imino-1,3-dithietane hydrochloride and 24.5 g. of isopropyl chloroformate was added 3.3 g. of powdered sodium acetate in small portions. After stirring for about one hour, the mixture was diluted with 50 ml. of benzene and stirred another hour. An ice-water mixture was added and mixing continued for two hours. The benzene phase was separated and the water extracted with fresh benzene. After combining and drying the benzene extracts, evaporation left 5.4 g. of off-white crude product. Recrystallization from hexane afforded 2.5 g. of white solid, m.p. 72.0°-73.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[C:43]1([CH3:52])[C:44]([N:49]=[C:50]=[S:51])=[CH:45][CH:46]=[CH:47][CH:48]=1>CN(C=O)C>[C:43]1([CH3:52])[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[S:51]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1ccccc1N=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3ccccc3C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 131.4 %

Procedure:
To a DMF solution (2 ml) of ice-cooled bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol), 60% oily NaH (18 mg) was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, o-tolyl isothiocyanate (59.8 μl, 0.445 mmol) was added, followed by further stirring for 2 hours. The reaction mixture was ice-cooled, and quenched with water (1 ml). This was diluted with dichloromethane (10 ml), and washed with water (10 ml×2). After the organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid o-tolylamide as a brown solid (134 mg). The PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-210) as a yellow powder (35.9 mg, 54%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][N:10]=[C:4]2[CH:3]=1.B([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24]([OH:26])=[O:25])(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCO>COCCOC.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([OH:26])=[O:25])=[CH:3][C:4]2=[N:10][N:9]=1
Reactant: Cc1ccc(C(=O)O)cc1B(O)O
Reactant: Clc1ccn2c(-c3ccccc3Cl)nnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Temperature: 25 °C

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridine (1.77 g, 6.7 mmol), 3-borono-4-methylbenzoic acid (1.57 g, 8.7 mmol), Pd(PPh3)2Cl2 (0.329 g, 0.46 mmol, Strem), and sodium carbonate (2.13 g, 20 mmol, JT Baker) in DME:EtOH:H2O=7:2:3 (8 ml) was heated to 80° C. for 8 h. The mixture was cooled to room temperature, diluted with MeOH and filtered through Celite. The filtrate was concentrated to yield the title compound as a brown solid. MS (ESI, pos. ion) m/z: 364.0 (M+1).