Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C.CCOCC.O([NH2:10])C.[Li][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2>CCCCCC>[NH2:10][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH:19]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2
Reactant: [Li]c1cccc2c1CC(N(CCC)CCC)CC2
Reactant: CON
Agent: [Li]C
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCN(CCC)C1CCc2cccc(N)c2C1
Temperature: -15 °C

Procedure:
A stirred solution (9.2 ml) of 0.92M MeLi in ether (8.5 mmol) of methoxylamine in hexane (9 ml) was added dropwise (1 drop/s) followed by 2.6 ml (4.3 mmol) of a 1.55M solution of 5, 6, 7 or 8-lithio-2-(di-n-propylamino)tetralin (prepared from 5, 6, 7 or 8-bromo-2-(di-n-propylamino)tetralin and n-BuLi). The mixture was warmed to -15° C. for 2 hr and quenched with water (0.5 ml). Workup of the resulting mixture afforded the desired 5, 6, 7 or 8-amino-2-(dinpropylamino)tetralin.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CO>CC(C)=O>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
The free base (0.32 g; 0.2914 mmol) was dissolved in acetone (10 mL) and treated with 0.1M L-tartaric acid in MeOH (2.9 mL; 0.29 mmol). This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a white solid; mp 178°-180° C.; IR (KBr) 3440, 3064, 3030, 2934, 2802, 1662, 1610, 1582, 1518, 1486, 1452, 1372 cm-1 ; MS (FAB) MH+ m/z 1099, (M+Na)+ m/z 1121, (M+K)+ m/z 1137; 1H-NMR (CDCl3) δ 1.119 (s, 3H), 1.217 (s, 3H), 1.518 (m, 7H), 1.667 (s, 3H), 1.873 (m, H), 1.957 (s, 3H), 2.111 (m, H), 2.215 (s, 3H), 2.316 (m, H), 2.432 (s, 3H), 2.597 (m, H), 2.875 (m, 2H), 3.684 (m, 2H), 3.816 (d, H), 4.196 (d, H), 4.370 (d, H), 4.440 (m, H), 4.975 (d, H), 5.665 (m, 2H), 6.030 (m, H), 6.252 (t, H), 6.284 (S, H), 7.096 (d, NH), 7.200-8.700 (m, 19H) .
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:12][C:13]1[CH:14]=[N+:15]([O-])[C:16]2[C:17](=[O:28])[C:18]3[C:23]([C:24](=[O:27])[C:25]=2[CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:14]1[C:13]([CH3:12])=[CH:26][C:25]2[C:24](=[O:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[N:15]=1)[CH3:31]
Reactant: Cc1cc2c([n+]([O-])c1)C(=O)c1ccccc1C2=O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOc1nc2c(cc1C)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
5 portions of 0.08 g (0.42 mmol of tosyl chloride were added to an agitated solution of 100 mg. (0.42 mmol) of 3-methyl-1-azaanthracen-9,10-dione 1-oxide in absolute ethanol at 75°-78° C. for 1 hour. Then the mixture was agitated at room temperature overnight and a yellow solid (58 mg, 0.22 mmol) corresponding to the compound (I-b) (yield 52%) was filtered. The starting product was recovered from the water by means of silica gel column chromatography eluting with ethyl acetate: ethanol (9:1): m.p. 186°-188° C. (the sublime compound around 170° C.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[H-].[Na+].[Br-].C(O[C@@H:46]1[C@@H:52](OC(=O)C)[C@H:51](OC(=O)C)[C@@H:50]([CH2:61]OC(=O)C)O[C@@H:47]1O)(=O)C>>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:7][C@@H:8]1[O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]1[CH:27]=[C:26]([C:47]2[CH:46]=[CH:52][CH:51]=[CH:50][CH:61]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(=C/c1cccc(-c2ccccc2)c1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 16 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-arylphenyl)-2-oxopropanoate (B14) (100 mg, 0.373 mmol), sodium hydride (9.0 mg, 0.373 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (153 mg, 0.373 mmol). The compound was isolated in the form of white solid in 16% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound T2.6 (1.10 g, 3.37 mmol) and a catalytic amount of DMF (0.10 mL) in DCM (12.0 mL), was slowly added thionyl chloride (0.802 g, 6.74 mmol) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue was purified by CombiFlash®® silica gel column chromatography eluting with hexane/EtOAc, 100/0 to 95/5) to give the title compound T2 (1.15 g). 1H NMR (400 MHz, CDCl3) δ ppm. 7.32-7.39 (m, 2H), 7.28-7.29 (m. 1H), 6.88 (t, 1H), 6.80-6.82 (m, 2H), 5.56 (s, 1H), 4.66 (s, 2H), 3.78 (s, 3H), 2.27-2.29 (m, 2H), 1.69 (t, 2H), 0.89 (s, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3=[N:14][C:15]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:17]=[C:12]3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](OCC)(OCC)(OCC)[CH3:23].N12CCCN=C1CCCCC2>C(O)CCC>[CH3:22][C:23]1[O:19][C:18]([C:15]2[N:14]=[C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][O:11][C:12]3=[CH:17][CH:16]=2)=[N:20][N:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)nc23)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCO
Product: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)nc23)cc1
Yield: 68.2 %

Procedure:
A solution of 3-[4-(methylthio)phenyl]furo[3,2-b]pyridine-5-carbohydrazide (0.20 g, 0.68 mmol) and triethyl orthoacetate (0.27 mL, 1.49 mmol) in n-butanol (5 mL) was heated under reflux for 1.5 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.68 mmol) was added to the reaction mixture, and the mixture was further heated under reflux overnight. After cooling, the precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.15 g, yield 67%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([NH2:9])[CH:8]=1.Cl[C:18]1[CH:27]=[CH:26][N:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:7]([NH:9][C:18]2[C:19]3[C:24](=[N:23][C:22]([CH3:28])=[CH:21][CH:20]=3)[N:25]=[CH:26][CH:27]=2)[CH:8]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(Sc2ccccc2)c(N)c1
Product: COc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 9b (69 mg, 0.30 mmol) was reacted with the product from Example 1d (53 mg, 0.30 mmol) following the procedure from Example 1g giving the title compound as a hydrochloride salt after trituration with solid (119 mg, 96%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3H) 3.83 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.07 (m, 7H) 7.57 (d, J=8.46 Hz, 1H) 7.76 (d, J=8.46 Hz, 1H) 8.85 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.46 Hz, 1H) 11.16 (br s, 1H) 14.43 (brs, 1H); MS (ESI+) m/z 374 (M−Cl)+; (ESI−) m/z 372 (M−HCl)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: O=C(O)c1ccccc1
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 75 %

Procedure:
Compound 35 was synthesized using a procedure similar to that described in Example 29 from 8a using benzoic acid to afford 0.19 g (75%) of 35 as a white crystalline solid, mp 223-225° C.; 1H NMR (CDCl3): δ 1.13 (3H, s); 1.40 (1H, dd, J=11.6, 13.1); 1.50 (3H, s); 1.64 (2H, m); 1.84 (1H, dd, J=2.9, 11.3); 2.10 (2H, m); 2.37 (1H, ddd, J=3.0, 4.2, 12.3); 2.45 (1H, m); 2.50 (1H, m); 2.62 (1H, s); 3.01 (1H, dd, J=4.4, 12.5); 3.73 (3H, s); 5.00 (1H, dd, J=3.0, 3.0); 5.52 (1H, dd, J=4.7, 11.4); 6.32 (1H, dd, J=0.8, 2.0); 7.32 (1H, m); 7.36 (1H, dd, J=1.8, 1.8); 7.50 (2H, m); 7.65 (1H, tt, J=1.6, 7.5); 8.03 (2H, m); 13C NMR (CDCl3): δ15.6, 16.2, 18.3, 31.3, 35.2, 38.9, 43.4, 43.6, 51.4, 51.4, 52.1, 61.8, 72.2, 77.5, 108.5, 125.7, 129.0, 129.0, 129.9, 134.1, 139.3, 143.8, 165.4, 171.4, 172.2, 204.8; anal. C 67.85%, H 6.14%, O 25.70%, calcd for C28H30O8, C 68.00%, H 6.11%, O 25.88%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C:28]3[CH:41]=[CH:40][C:31]([O:32][CH2:33][C:34](N(OC)C)=[O:35])=[CH:30][CH:29]=3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:35][CH:34]([CH3:43])[CH2:33][O:32][C:31]1[CH:30]=[CH:29][C:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)=[CH:41][CH:40]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(=O)N(C)OC)cc2)c2ccnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(C)O)cc2)c2ccnn12
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 2-(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}phenoxy)-N-methoxy-N-methylacetamide (0.44 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.6 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (4 mL), and sodium borohydride (0.030 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.30 g, 73%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([Cl:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[Cl:23][C:24]1[C:25]([C:30](O)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:30]([C:25]1[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: O=C(O)c1ncccc1Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3Cl)ccc21
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(CNC(=O)c4ncccc4Cl)c3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 218) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as an off-white solid. MS: 441.3 (M+H+).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH2:30][CH3:31]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH2:30][CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-butyramidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.15 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [C:1]([O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]([CH3:24])[C:13]=1[C:25]([OH:27])=O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(OCC)C>[C:1]([O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15](=[O:23])(=[O:22])[N:14]([CH3:24])[C:13]=1[C:25]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[O:27])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccn1
Reactant: CN1C(C(=O)O)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CN1C(C(=O)Nc2ccccn2)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O

Procedure:
The cinnamoyl anhydride and the other mixed anhydrides of 4-cinnamoyloxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide prepared respectively according to Example 12 or Example 13 are directly reacted, without previous purification or recovery from their methylene chloride solution, with 2-2.5 molar equivalents of 2-aminopyridine with stirring and external cooling. After dilution with 3 volumes of diethyl ether the reaction mixture is stirred at 15° C. for 3 hours, then the procedure of Example 16 is repeated obtaining the desired 4-cinnamoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:11][CH:12]1[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])(C2C=CC=CC=2)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:11][C@H:12]2[CH2:13][CH2:14][Si@H:15]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(F)c1
Reactant: FCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: FCCCC[Si@H]1CC[C@H](COc2ccc(F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3,4-difluorophenol and 4-bromomethyl-1-(4-fluorobutyl)-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[N:3]=1.C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:5]([Br:25])=[C:4]([CH3:19])[N:3]=1
Reactant: BrBr
Reactant: Cc1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)c2[nH]c(=O)n(Cc3ccccc3)c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-1-benzyl-6-methyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (20 mg, 0.08 mmol) was suspended in 5 mL of acetic acid then sodium acetate (5 mg, 0.08 mmol) was added followed by bromine (4□L, 0.08 mmol) dropwise. The mixture was stirred at room temperature for 30 minutes. The mixture was diluted in water (50 mL) and extracted with ethyl acetate (50 mL), the organic layer was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 10% of methanol in ethyl acetate to give 15 mg of the title compound as a brown solid.
Reaction SMILES: [CH3:1][NH2+:2][CH3:3].[F:4][C:5]([F:15])([F:14])[C:6]1[CH:7]=[C:8]([NH:12][NH2:13])[CH:9]=[CH:10][CH:11]=1.CNC>CCOCC>[F:4][C:5]([F:14])([F:15])[C:6]1[CH:7]=[C:8]([N:12]2[CH:3]=[N:2][CH:1]=[N:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: C[NH2+]C
Agent: CNC
Solvent: CCOCC
Product: FC(F)(F)c1cccc(-n2cncn2)c1
Temperature: 60 °C

Procedure:
A mixture of 16.4 g of 2A and 17.6 g of 3-trifluoromethylphenylhydrazine were stirred and heated to 60° C. Dimethylamine was evolved in an exothermic reaction and the temperature maintained at 90° C. until evolution ceased (about 30 minutes). After cooling, the reaction mixture was dissolved in ether, washed with water, dried and chromatographically purified to yield 1-(3-trifluoromethylphenyl)-1,2,4-triazole (2B).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:32]>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([C:21]([NH2:32])=[O:22])=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(C(=O)O)n3)nc2N1C1CCCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(C(N)=O)n3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-3-carboxylic acid (Example 56) used instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44) and ammonium acetate instead of dimethylamine hydrochloride. LCMS: 370.1 m/z (M+H)+; ret. Time: 3.39 min (Analytical Method A).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([SH:34])=[N:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([S:34][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:23])=[N:4][CH:3]=2)=[N:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1cnc(S)n1C
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCOCC2)CC1
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCOCC3)C3CCC(C)CC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea (Example 203) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1.[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>>[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=4[N:7]=[CH:6]3)[CH2:30][CH2:29]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Reactant: c1ccc(SCCCN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)c2c(ncn2CCCN2CCN(CCCSc3ccccc3)CC2)n(C)c1=O

Procedure:
7-(3-Chloropropyl)-theophylline (1 mole) and 1-(3-phenylthiopropyl)-piperazine are refluxed for 24 hours in a 50% aqueous-alcoholic solution. On completion of the reaction, sodium hydroxide (1 mole) is then added. The mixture is extracted with methylene chloride and washed with water, after which the solvent is evaporated off and the residue is recrystallized from ethanol.
Reaction SMILES: C([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:7][CH:6]=1)(=O)C.Cl>CO.O1CCOCC1>[F:18][C:13]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]2[CH:19]=[CH:20][C:5]([OH:4])=[CH:6][CH:7]=2)[CH:16]=[C:15]([OH:17])[CH:14]=1
Reactant: CC(=O)Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3-fluoro-4′-acetoxystilbene (1.09 g, 3 mmol) in dry CH2Cl2 (120 mL) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water, dried over Na2SO4, filtered and evaporated. The 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 61%) was obtained as white solid. To a solution of the crude 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 1.8 mmol) in MeOH (7.5 ml) was added 3.7 ml 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3-fluoro-5,4′-dihydroxystilbene (0.33 g, 780%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.624 (s, 2H), 7.46 (m, 2H), 7.06 (q, 2H), 6.84 (m, 4H), 6.66 (dt, 1H); 13C NMR (Aceton-d6, 75 MHz) δ 164.90 (d), 159.96 (d), 158.57, 142.02 (d), 130.84, 129.63, 129.10, 125.55 (d), 116.53, 110.28 (d), 104.44 (d), 102.00 (d); 19F NMR (Aceton-d6, 282 MHz) δ-32429.72 (t); HRMS (EI+) found 230.0738, calcd 230.0743 for C14H, FO2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon 2.10 g (7.85 mmol) of methyl 2-(3-chloropyridin-2-yl)-5-hydroxymethyl-2H-pyrazole-3-carboxylate are introduced in 13 ml of dichloromethane and this initial charge is cooled to 0° C. and admixed dropwise in succession with 1.64 ml (11.8 mmol) of triethylamine and 0.67 ml (8.63 mmol) of methanesulphonyl chloride. It is stirred at this temperature for 30 minutes, diluted with 50 ml of dichloromethane and washed successively with 50 ml each of saturated aqueous sodium hydrogen sulphate solution, 10 percent strength aqueous hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.