Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4-Methoxy-phenyl)-pyridin-2-yl-methanone (10.0 g, 0.046 mol) in DCM(140 mL) was added boron tribromide (17.8 mL, 0.187 mol) at −78° C. slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. Reaction mixture was quenched with saturated Sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2×250 mL). The organic layer was dried over sodium sulphate and concentrated. Purification by 100-200-mesh sized silica gel column with 0-40% EtOAc:Hexane as eluent provided the product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:15][CH2:16][CH:12]([OH:11])[CH2:13]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: OC1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(N2CCC(O)C2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 2-chloro-5-nitro-pyrimidine (638 mg, 4 mmol) in THF (15 mL) cooled to 0° C. was added 3-hydroxypyrrolidine (392 mg, 4.5 mmol) and triethylamine (1.2 mL). The mixture was stirred at room temperature overnight. Solids were filtered out and the solution was concentrated. The residue was dissolved in ethyl acetate and extracted with water. Organic layer was washed with dilute aqueous citric acid solution. After the evaporation of solvents, the residue was treated with ether and the yellow solid was filtered to give N-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol (570 mg). LCMS calcd for C8H10N4O3 m/e 210.19, obsd 211.0 (ES, M+H). Hydrogenation of the nitro compound, as above, provided N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1>CCOCC>[F:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]([CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[OH:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cnc2sc3cc(F)ccc3n12
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCc1ccccc1)c1cnc2sc3cc(F)ccc3n12

Procedure:
Magnesium (0.146 g) in anhydrous ether (15 mL) was treated with (2-bromoethyl)-benzene (0.82 mL) and reacted for 2.5 hours. The Grignard reagent was treated with solid 7-Fluoro-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3) (0.44 g). Incomplete conversion was observed, an additional charge of Grignard reagent was added, and reacted for 24 hours. The reaction mixture was decanted into 5% ammonium chloride solution and extracted with ethyl acetate. The extract was washed, dried, and evaporated to a solid residue (0.60 g) of crude 7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol (Formula L-4). Crystallization from isopropanol solution gave pure 7-Fluoro-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol (Formula L-4), m.p. 195-196°. Anal. Calcd for C18H15FN2OS. C, 66.24; H, 4.63; N, 8.58; S, 9.82. Found: C, 66.08; H, 4.64; N, 8.48; S, 9.72. MS m/z 326 (M+), 235, 221, 205, 193, 179, 193, 179, 166, 152, and 91. IR (mull). 3301, 1547, 1486, 1321, 1260, 1208, 1200, 1133, and 1039 cm−1. NMR (CDCl3/CD3OD) δ2.33 (q, J=7.6 Hz, 2, CH2), 2.76-3.0 (m, 2, CH2), 5.00 (t, J=7.6 Hz, 1, CH), 7.1-7.4 (m, 9, ArH, CH), 8.01 (m, 1, ArH).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][O:9]2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)OCC=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)OCCC2

Procedure:
7-Fluoro-2H-chromene (4.17 g, 27.8 mmol) and Pd/C (500 mg, 10 wt %) in ethyl acetate (70 mL) was stirred under hydrogen at 60 psi for 6 hours. The reaction was filtered through a pad of Celite™ and concentrated under reduced pressure to give the desired product as the major regioisomer in a 3:1 mixture of regioisomers as a yellow oil. This material was used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=6.97 (t, J=7.5 Hz, 1 H), 6.57-6.49 (m, 1 H), 4.21-4.16 (m, 2 H), 2.76 (t, J=6.4 Hz, 2 H), 2.05-1.98 (m, 2 H); LCMS (m/z) ES+=152 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:36])([CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[CH:10]([N:12]1[C:17](=[O:18])[C:16]2[S:19][C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)=[CH:21][C:15]=2[N:14]=[CH:13]1)[CH3:11].[CH3:37][OH:38]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:36])([CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[C@H:10]([N:12]1[C:17](=[O:18])[C:16]2[S:19][C:20]([C:22]3[CH:29]=[CH:28][C:25]([C:26](=[NH:27])[O:38][CH3:37])=[CH:24][CH:23]=3)=[CH:21][C:15]=2[N:14]=[CH:13]1)[CH3:11]
Reactant: CC(n1cnc2cc(-c3ccc(C#N)cc3)sc2c1=O)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CO
Solvent: ClC(Cl)Cl
Product: COC(=N)c1ccc(-c2cc3ncn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c(=O)c3s2)cc1
Reaction time: 8 h
Yield: 94 %

Procedure:
To a cooled (0° C.) solution of (1R,2R)-(4-[3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl]benzonitrile (1.03 g, 2.04 mmol) (obtained in example 32) in MeOH (25 mL) and CHCl3 (5 mL) was bubbled HCl gas until saturation. The reaction mixture was allowed to stand at 0° C. overnight, and was then concentrated and poured to aqueous K2CO3 solution. CHCl3 was added, the organic phase was separated and the aqueous phase was reextracted with CHCl3. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (1.03 g, 94%): mp 194°-201° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.60 (s, 1H, N=CH--N), 7.78 (s, 1H, triazole), 7.77 (s, 4H, arom), 7.74 (s, 1H, triazole), 7.60 (s, 1H, thiophene), 7.49 (dt, Jd =6.4, Jt =8.8, 1H, arom), 6.9-6.7 (m, 2H, arom), 5.98 (q, J=7.3, 1H, MeCH), 5.56 (broad s, 1H, OH), 5.20 (d, J=14.2, 1H, CH(H)), 4.02 (d, J=14.2, 1H, CH(H)), 3.97 (s, 3H, OCH3),1.32 (d, J=7.3, 3H, CHMe).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15](=[O:21])[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH2:14][C:15]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:21])[CH:11]=[CH:12][CH:13]=1
Reactant: CCN(CC)C(=O)Cc1cccc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Cc1cccc(N)n1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
(6-Diethylcarbamoylmethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.2 g) in CH2Cl2 (10 mL) was treated at RT with trifluoro-acetic acid (0.5 mL) and the solution was stirred for 1.5 h until the reaction was complete according to the analysis. The mixture was allowed to warm to 10° C. and partitioned between aqueous diluted KHCO3 and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered, evaporated to give 2-(6-amino-pyridin-2-yl)-N,N-diethyl-acetamide (148 mg) as a light yellow solid that was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.[S-:31][C:32]#[N:33].[K+].BrBr>>[NH2:33][C:32]1[S:31][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=4)[CH:10]=[CH:11][C:12]=3[O:13][CH3:14])[CH:29]=[CH:30][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Yield: 79.6 %

Procedure:
Using N-[3-(4-aminophenoxy)-4-methoxyphenyl]-3-(1-cyano-1-methylethyl)benzamide (1.10 g, 2.74 mmol), potassium thiocyanate (0.97 g, 10.0 mmol) and bromine (0.60 g, 3.75 mmol), and in the same manner as in Example A18(iv), the title compound (1.00 g, 80%) was obtained as a yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[F:20])[NH:5][CH:4]=1)[CH3:2].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]4[NH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:11]=34)=[C:14]([F:20])[CH:15]=2)[CH:27]=1
Reactant: CCc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
50 mg (0.18 mmol) of 4-[(3-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoroaniline and 32 mg (0.19 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 27 μl of 37% strength hydrochloric acid are added, and the mixture is heated at reflux overnight. Using 1N aqueous sodium hydroxide solution, the pH is then adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and purified by preparative HPLC.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C(N(CC)CC)C>[Cu]I.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.O1CCCC1>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.096 g, 0.38 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.094 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) the title compound was obtained (0.137 g, 90%). 1H NMR (300 MHz, CDCl3): δ 7.47 (d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.24 (d, 2H, J=7.9 Hz), 6.82 (d, 1H, J=2.1 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[C:12](Cl)([Cl:14])=[S:13]>>[Cl:14][C:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[S:13]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)C1CCCCN1
Product: CCOC(=O)C1CCCCN1C(=S)Cl

Procedure:
In the same way, 3-[2-(4-chlorobenzyloxy)-5-pyridyl]-1,5-tetramethylene-4-thiohydantoin is prepared by reacting 2-ethoxycarbonylhexahydropyridine with thiophosgene to give N-chlorothiocarbonyl-2-ethoxycarbonylhexahydropyridine, which is then reacted with 2-(4-chlorobenzyloxy)-5-aminopyridine.
Reaction SMILES: C([Si]([O:8][CH2:9][CH:10]1[O:14][C:13]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[CH:21]=[CH:22][C:12]=2[CH2:11]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:14]1[CH:10]([CH2:9][OH:8])[CH2:11][C:12]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:13]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2ccc3c(c2O1)CCCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCC1Cc2ccc3c(c2O1)CCCC3
Yield: 66.4 %

Procedure:
Treatment of (±)-tert-butyl(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethoxy)dimethylsilane (4.38 g; 0.014 mol) with tetrabutylammonium fluoride (16.5 mL, 1.0 M solution in tetrahydrofuran) generally according to the procedure described for Intermediate 6 afforded 1.9 g (67%) of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethanol as a colorless oil. Rf=0.12 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C13H16O2.0.1H2O: C, 75.77; H, 7.92. Found: C, 75.77; H, 7.93.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:19](Cl)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:19]([NH:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)C=Cc1ccccc1)C(C)=O
Reaction time: 0.33 h

Procedure:
Triethylamine (8.3 ml) was added dropwise to a solution of ethyl 2-aminoacetoacetate hydrochloride (5.43 g) and cinnamoyl chloride (5.0 g) in chloroform (90 ml) with ice-cooling and stirring. After 20 minutes, the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was treated with isopropyl ether to give ethyl 2-cinnamoylaminoacetoacetate as crystals; yield 6.1 g (73.9%). Recrystallization from ethanol gave colorless needles melting at 113°-114° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[Na+].[I-].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][C:2]([CH3:4])([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
Ethyl iso-butyrate (35.0 g, 0.30 mol) was added to a solution of lithium N,N-diisopropyl amide (prepared from N,N-diisopropylamine (38.1 g, 0.38 mol) and n-BuLi (207 mL, 0.33 mol, 1.6 M solution in hexanes)) in dry tetrahydrofuran (1 L) at −78° C. over a 30 min period under N2 atmosphere. After the addition was complete, the reaction was stirred for 1 h after which HMPA (100 mL), NaI (67.0 g, 0.44 mol) and 4-methoxybenzyl chloride (39.3 g, 0.25 mol) were added sequentially. The reaction was then warmed to room temperature and stirred for additional 16 h before quenching at 0° C. with saturated NH4Cl solution (250 mL) and the mixture was extracted with EtOAc (2×1 L). The combined organic layers were washed successively with 2 N HCl (2×300 mL), saturated sodium bicarbonate solution (2×300 mL), and brine (400 mL), dried over Na2SO4 and filtered. Concentration of the filterate and purification of the resulting residue by flash column chromatography (silica gel, 100:0 to 96:4 hexane/EtOAc) afforded 54.0 g (90%) of ethyl 2,2-dimethyl-3-(4-methoxyphenyl)propanoate as a light yellow oil; 1H NMR (200 MHz, CDCl3) δ 7.03 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 4.10 (q, J=7.3 Hz, 2H), 3.78 (s, 3H), 2.78 (s, 2H), 1.23 (t, J=7.3 Hz, 3H), 1.15 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[CH:17]=2)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=2)[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2cc(C(=O)OCc3ccccc3)ccc2c1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2,6-Naphthalenedicarboxylic acid monobenzyl ester (2.9 g, 9.5 mmol) in anhydrous THF (50 ml) under N2 at 0° C., was added 1.0M BH3.THF (14.3 ml, 14.3 mmol). The mixture was stirred at room temperature for overnight, then partitioned between brine (200 ml) and EtOAc (3×75), dried over Na2SO4, and taken to dryness to yield a white solid (6-Hydroxymethyl-2-naphthalenecarboxylic acid benzyl ester, 2.6 g). 1H NMR (360 MHz, DMSO-d6): δ 8.635 (s, 1H, Ar—H), 8.110 (d, J=8.6 Hz, 1H, Ar—H), 8.004 (m, 2H, Ar—H), 7.919 (s, 1H, Ar—H), 7.574-7.366 (m, 6H, Ar—H), 5.425-5.393 (m, 2H, —COOCH2—), 4.71-4.696(d, J=5.2 Hz, 2H, HO—CH2—), MS m/e 291 [M+−1].
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=O)C.[C:18]([CH:23]=[C:24]1[CH2:28]C[CH2:26][NH:25]1)([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:21]([O:20][C:18]([C:23]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]2[N:25]([CH2:26][CH2:4][CH2:5]2)[C:24]=1[CH3:28])=[O:19])[CH3:22]
Reactant: CCOC(=O)C=C1CCCN1
Reactant: CCOC(=O)CC(=O)C=Cc1ccccc1C
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCCC2=C(C(=O)OCC)C1c1ccccc1C
Yield: 62 %

Procedure:
Upon boiling a solution of 7.7 g of 2-methylbenzylideneacetoacetic acid ethyl ester and 5.6 g of carbethoxymethylidenepyrrolidine in 50 ml of ethanol for 8 hours, 5-methyl-7-(2-methylphenyl)-1,2,3,7-tetrahydroindolizine-6,8-dicarboxylic acid diethyl ester of melting point 148° (alcohol) is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26].ClC1C=CC=C(C(OO)=[O:35])C=1>>[OH:1][CH2:2][CH2:3][N:4]1[C:24](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[S:13](=[O:35])[C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=4[N:6]([C:7]=23)[C:5]1=[O:26]
Reactant: O=c1c2cccc3c2n(c(=O)n1CCO)-c1cc(C(F)(F)F)ccc1S3
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=c1c2cccc3c2n(c(=O)n1CCO)-c1cc(C(F)(F)F)ccc1S3=O

Procedure:
When 2-(2-hydroxyethyl)-10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione was oxidized with m-chloroperbenzoic acid as described in the procedure of Example 6, the title compound was obtained, m.p. 205-206° (ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[Br:12][C:13]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:15][C:14]=1[Cl:22].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O>[Br:12][C:13]1[CH:17]=[C:16]([S:18]([NH:1][C:2]2[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])(=[O:20])=[O:19])[S:15][C:14]=1[Cl:22]
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Yield: 53 %

Procedure:
A solution of 3-aminosalicylic acid (0.17 g, 1.11 mmol) and 3-bromo-2-chlorothiophene-5-sulfonyl chloride (0.33 g, 1.11 mmol) in aqueous dioxane (20 mL, 95:5 dioxane/water) was stirred at room temperature for 4 weeks. The pH of the reaction mixture was adjusted to about 9 using 1M Na2CO3 and then EtOAc (200 mL) and water (100 mL) were added. The organic phase was removed and the aqueous phase washed with more EtOAc. The pH of the aqueous phase was adjusted to about 3 with concentrated phosphoric acid and EtOAc (200 mL) was added. The aqueous phase was removed and the organic phase was washed with 1 M HCl and brine, dried over MgSO4, filtered and concentrated. The brown residue was recrystallized from aqueous MeOH at 60° C. The precipitate was collected by filtration and dried over night. The title compound was obtained in 53% yield (0.24 g). 1H NMR (500 MHz, MeOH-d4) δ ppm 6.92 (t, J=7.93 Hz, 1 H) 7.34 (s, 1 H) 7.65 (dd, J=7.93, 1.59 Hz, 1 H) 7.75 (dd, J=7.93, 1.59 Hz, 1 H). MS (ESI+) m/z 412 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.ClCCCl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O>[C:19]([O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(OC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.0 g) was mixed with DCE (30 ml), and TEA (3.0 ml) and benzoyl chloride (2.4 g) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (10 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain piperidin-4-yl benzoate (3.1 g).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])C.COC1C=C(C=CC=1O)C#N>>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8]
Reactant: CCOc1cc(C#N)ccc1O
Agent: COc1cc(C#N)ccc1O
Product: N#Cc1ccc(O)c(O)c1
Yield: 79 %

Procedure:
The preparation was carried out according to the process of Example 2a except that 3-ethoxy-4-hydroxybenzonitrile was used as the starting material instead of 3-methoxy-4-hydroxybenzonitrile. 3,4-Dihydroxybenzonitrile was obtained as a white solid with a yield of 79% and a purity of greater than 98% as indicated by HPLC analysis.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1.O>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Fc1cncc(F)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at −78° C. under nitrogen (N2). The solution was stirred for 30 min at −78° C., then a solution of 3,5-difluoropyridine (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at −78° C. for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl ether (350 mL) and washed successively with water (2×200 mL), saturated sodium chloride solution (1×150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88%). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+): 406.