Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+].[Na+].[NH2:10][C:11]1[N:16]=[CH:15][C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1>O.C(O)C>[NH2:10][C:11]1[NH:16][CH:15]([S:1]([OH:4])(=[O:3])=[O:2])[C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1nc(C)c2n1N=C(N)NC2S(=O)(=O)O

Procedure:
Sodium metabisulphite (1.5 g.) in water (45 ml.) was added to 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.) in ethanol (20 ml.). The solid was collected and dried and had m.p. 232°-234°.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5](=[O:14])[C:6]=1[N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[C:5]1=[O:14]
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: CN1C(=O)C(Br)=C(N2CCC(=O)CC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(N2CCC(=O)CC2)C1=O
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a room temperature, stirred solution of 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was added 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (151 mg, 0.41 mol) under a N2 atmosphere. The reaction mixture was stirred for 30 minutes and then Na2CO3 (87 mg, 1.04 mmol), water (4 mL) and Pd(PPh3)4 (40 mg, 0.03 mmol) were added also under a N2 atmosphere. The resulting mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1-methyl-3-(4-oxopiperidin-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (80 mg, 52%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J=7.4 Hz, 1H), 8.12 (t, J=7.2 Hz, 2H) 7.79 (t, J=7.2 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.62-3.58 (m, 4H), 2.96-2.85 (m, 4H), 2.56 (s, 4H). MS: M+: m/z=441.6; M+H: m/z=442.7. HPLC: 97%, (Condition-B).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]([CH2:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(O)C>[CH2:2]([N:9]1[C:13]([CH2:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(CCc1cncn1Cc1ccccc1)=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(Cn2cncc2CCCC(c2ccccc2)c2ccccc2)cc1

Procedure:
1-benzyl-5-(4,4-diphenyl-3-butenyl)-1H-imidazole hydrochloride salt is hydrogenated in ethanol as described in Example 1 c). M.p. of the product as hydrochloride is 200°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCO)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure O and Scheme W using 4-(4-methoxyphenyl)-1-butanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].[CH2:14](O)[CH2:15]C>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:14]=[CH2:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CCCO
Reactant: CCOc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc([N+](=O)[O-])c(OCC)c1
Temperature: 100 °C
Yield: 81 %

Procedure:
To 5-bromo-2-nitrophenyl ethyl ether (8.8 g, 35.76 mmol) in 80 mL of n-propanol was added, PdCl2(dppf)*DCM (0.523 g, 0.72 mmol), potassium ethenyl(trifluoro)borate (6.71 g, 50 mmol), and TEA (3.61 g, 35.76 mmol). The mixture was heated to 100° C. for 3 h. The solvent was rotovaped down and the residue dissolved in DCM, and filtered to remove insoluble solids. 20 g of silica gel was added and the solvent rotovaped down, and purified by flash chromatography to give the title compound of step B (5.58 g, 28.89 mmol, 81%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J=8.97 Hz, 1H), 7.01-7.03 (m, 1H), 6.68 (dd, J=17.67, 10.71 Hz, 1H), 5.84 (d, J=17.58 Hz, 1H), 5.44 (d, J=11.17 Hz, 1H), 4.19 (q, J=6.96 Hz, 2H), 1.47 (t, J=6.96 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:4]=2[C:3]=1[C:12]#[N:13].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>CS(C)=O>[CH3:11][C:10]1[C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[S:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Cc1cccc2sc(N)c(C#N)c12
Solvent: CS(C)=O
Product: Cc1cccc2sc(Nc3ccccc3[N+](=O)[O-])c(C#N)c12
Yield: 92.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-4-methylbenzo[b]thiophene-3-carbonitrile (3.8 g), 2-chloronitrobenzene(3.5 g) and dimethyl sulfoxide (45 ml), 4-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile (5.8 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C:13]([NH:17]C(=O)OC(C)(C)C)([CH3:16])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH2:26]([C@@H:28]1[CH2:37][C:36]2[N:35]=[C:34]([CH3:38])[N:33]=[C:32]([N:39]3[CH2:45][C:44]4[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][C:43]=4[O:42][CH2:41][CH2:40]3)[C:31]=2[CH2:30][CH2:29]1)[CH3:27]>>[NH2:17][C:13]1([CH3:16])[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:47]3[CH:48]=[CH:49][C:43]4[O:42][CH2:41][CH2:40][N:39]([C:32]5[C:31]6[CH2:30][CH2:29][C@H:28]([CH2:26][CH3:27])[CH2:37][C:36]=6[N:35]=[C:34]([CH3:38])[N:33]=5)[CH2:45][C:44]=4[CH:46]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(B(O)O)cc3C2)C1
Product: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5CCC(C)(N)C5)c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using 1,1-dimethylethyl {1-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-3-methylpyrrolidin-3-yl}carbamate (reagent preparation 25) and {4-[(7S)-7-ethyl-2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.37 (s, 1H), 7.97 (s, 1H), 7.41 (s, 1H), 7.29 (d, 1H), 6.94 (d, 1H), 4.64 (m, 2H), 4.27 (m, 1H), 4.05 (m, 1H), 3.94 (m, 2H), 3.47 (m, 1H), 3.31 (m, 1H), 3.12 (m, 2H), 2.81 to 2.66 (m, 2H), 2.49 (m, 1H), 2.28 (s, 3H), 2.21 (m, 1H), 1.90 (m, 1H), 1.84 (m, 2H), 1.62 (m, 1H), 1.36 (m, 2H), 1.14 (s, 3H), 1.09 (m, 1H), 0.99 (t, 3H); MS (EI) for C30H39N7O3S: 578 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: ClCc1cccnc1
Reactant: O=Cc1ccc(O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2cccnc2)cc1O
Yield: 12.1 %

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (25 g), 3-picolyl chloride hydrochloride (38.2 g), potassium carbonate (91 g), potassium iodide (0.5 g) and tetra-n-butylammonium bromide (0.5 g) in methyl ethyl ketone (1000 ml) was heated at reflux for 4 hours. The reaction mixture was filtered and evaporated. The residue was partitioned between ethyl acetate and dilute acetic acid. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting initially with a mixture of pentane and ethyl acetate (3:1, v/v) then with a mixture of pentane and ethyl acetate (1:1, v/v) and finally with a mixture of pentane and ethyl acetate (85:15, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (5 g) as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]1[C:19](=[O:20])[CH2:18][NH:17][C:16](=[O:21])[CH:15]=[C:10]12)=O.[C:22]([NH2:25])(=[O:24])[CH3:23]>>[CH3:23][C:22]1[O:24][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[CH2:7][CH2:8][N:9]2[C:19](=[O:20])[CH2:18][NH:17][C:16](=[O:21])[CH:15]=[C:10]23)[N:25]=1
Reactant: CC(N)=O
Reactant: O=C1C=C2c3cccc(C(=O)CBr)c3CCN2C(=O)CN1
Product: Cc1nc(-c2cccc3c2CCN2C(=O)CNC(=O)C=C32)co1
Temperature: 130 °C
Yield: 53.9 %

Procedure:
111-3. A flask was charged with 9-(2-bromoacetyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (230 mg, 0.66 mmol) and acetamide (233 mg, 3.95 mmol) and the solid mixture was heated to 130° C. for 15 min. The resulting brown liquid mass was partitioned in AcOEt and H2O. The org. phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH (100:0 to 90:10) gave the title compound (110 mg) as a beige powder. UPLC-MS: MS 310.2 (M+H+); UPLC rt 0.67 min.
Reaction SMILES: [CH:1]1=[CH:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7]1.I([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl.CO>[CH:2]12[CH:1]=[CH:7][CH:6]([O:30][N:31]1[C:32]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:38])[CH2:5][CH2:4][CH2:3]2
Reactant: C1=CCCCC=C1
Reactant: CC(C)(C)OC(=O)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1OC2C=CC1CCC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
(1Z,3Z)-Cyclohepta-1,3-diene (3.54 g, 37.6 mmol) was dissolved in methylene chloride (36 mL) in a flask equipped with a dropping funnel under nitrogen. Tetrabutylammonium periodate (16.29 g, 37.6 mmol) was added and the reaction was cooled to 0° C. The dropping funnel was charged with tert-butyl hydroxycarbamate (5.01 g, 37.6 mmol) in methanol (30 mL). The contents of the funnel were added dropwise and stirring continued for 3 hours. The reaction was diluted with methylene chloride and transferred to a separatory funnel. The methylene chloride solution was washed sequentially with water and brine. The organic phase was then dried over magnesium sulfate. Filtration and evaporation provided the crude product. The material was purified on a 330 g ISCO silica gel column (0-70% ethyl acetate in hexanes). Evaporation of the product-containing fractions gave 23A (5.44 g, 64% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (ddd, 1H, J=9.2, 6.9, 0.8 Hz), 6.18 (ddd, 1H, J=9.1, 6.1, 1.1 Hz); 4.60-4.73 (m, 2H); 1.53-1.87 (m, 4H); 1.46 (dtt, 1H, J=14.1, 4.9, 4.9, 2.4, 2.4 Hz); 1.39 (s, 9H); 1.24 (qd, 1H, J=12.9, 6.0 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[N:6]([CH3:16])[N:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH2:42][CH3:43])[C:32]1=[O:33])[CH2:29][CH3:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:1]([C:4]3[CH:8]=[C:7]([O:9][CH2:10][C:11]([OH:13])=[O:12])[N:6]([CH3:16])[N:5]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH2:29][CH3:30])[C:32]1=[O:33])[CH2:42][CH3:43]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCOC(=O)COc1cc(C(=O)O)nn1C
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)n(C)n3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[3-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:1][C@H:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)=[O:15])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@H](C)Oc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
{circle around (1)}: A mixture comprising 1.25 g of (S)-4-(1′-methylheptyloxy)benzoic acid, 1.0 g of 4-benzyloxyphenol, 1.03 g of DCC and 10 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate under reduced pressure. The resultant residue was purified by means of silica gel column chromatography, whereby 2.21 g of (S)-4-[4′-(1″-methylheptyloxy)phenylcarbonyloxy)-1-benzyloxybenzene was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[C:30](=O)[C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>O.C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
That is, to the THF (20 mL) suspension of lithium aluminum hydride (577 mg, 15.2 mmol), aluminum chloride (2.03 g, 15.2 mmol) was added under ice cooling, and then the mixture was stirred for 10 minutes and added with the THF (25 mL) solution of 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-on (2.00 g, 5.07 mmol), and the mixture was stirred for 2 hours under reflux. After cooling the reaction solution on ice, water and 0.5 N aqueous solution of sodium hydroxide were serially added thereto. The mixture was stirred for 1 hour at room temperature, and then extraction was performed using ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After that, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate 90:10-75:25) and crystallized from ethyl acetate and hexane to obtain the title compound 1.60 g as a colorless crystal (yield 83%). Melting point was 152 to 155° C.
Reaction SMILES: [C:1]([C:5]([NH:7][C@@H:8]([C@@H:13]([C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[Cl:30])[N:16]=1)[CH3:14])[C:9]([O:11]C)=[O:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+]>O>[C:1]([C:5]([NH:7][C@@H:8]([C@@H:13]([C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[Cl:30])[N:16]=1)[CH3:14])[C:9]([OH:11])=[O:10])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](NC(=O)C(C)(C)C)[C@H](C)c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the ester from Step C (1 g, 2.11 mmol) in 50 mL of a 4:1 solution of tetrahydrofuran:water at 0° C. was added a solution of lithium hydroxide monohydrate (0.3 g, 6.33 mmol) in 8 mL of water. After stirring at 0° C. for 1 h, the THF was removed by evaporation under reduced pressure and 10 mL of 2N hydrochloric acid was added. The aqueous solution was extracted with three portions of ethyl acetate. The combined organic layers were washed with saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo to afford the product which was used in the next step without purification. LC/MS 360.0 (M+1-BOC).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: BrCCCN1CCCCC1

Procedure:
Combine piperidine (5.0 g, 58.7 mmol), fused sodium acetate (4.82 g, 58.7 mmol) and 1,3-dibromopropane (11.85 g, 58.7 mmol) and reflux for several hours. Pour the mixture into water and add sodium carbonate to create a basic pH. Remove the unreacted 1,3-dibromopropane by distillation. Extract the left-over residue with ether and evaporate to obtain the final, desired compound.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[OH:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[C:15]2[N:14]=[CH:13][C:12]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.[Br:41]Br.O>CCOCC>[Br:41][C:37]1[CH:38]=[C:33]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([N:17]=[CH:18][C:19]=3[C:20]3[CH:21]=[CH:22][C:23]([S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][CH:25]=3)[C:11]=2[OH:10])[CH:34]=[CH:35][C:36]=1[O:39][CH3:40]
Reactant: COc1ccc(-c2cnc3c(-c4ccc(Sc5ccccc5)cc4)cnn3c2O)cc1
Reactant: BrBr
Solvent: O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2cnc3c(-c4ccc(Sc5ccccc5)cc4)cnn3c2O)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2-ml nitrobenzene suspension of 420 mg of 7-hydroxy-6-(4-methoxyphenyl)-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine, 0.1 ml of bromine was added and stirred for 1 hour at room temperature, and water and ether were added, and the precipitate was filtered. It was washed with water, methanol, ethyl acetate and ether, dried, and the title compound was obtained (270 mg, 54%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N+:8]([C:11]1[C:12]([NH:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=2[NH:29][C:30](=O)OC(C)(C)C)=[N:15][CH:16]=1)([O-:10])=[O:9]>C(Cl)Cl>[N+:8]([C:11]1[C:12]([NH:37][CH:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)=[N:13][C:14]([N:17]2[C:18]3[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[N:29]=[CH:30]2)=[N:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1Nc1ncc([N+](=O)[O-])c(NC2CCOCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cnc(-n2cnc3ccc(OC(F)(F)F)cc32)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A freshly prepared solution of 30% TFA in DCM (25 mL) was added to the 1.0 g tert-Butyl 2-(5-nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-ylamino)-4-(trifluoromethoxy)phenylcarbamate and the solution were stirred at room temperature for 2 hrs. The solvents were removed in vacuo to yield an orange residue that was carried on without further purification (MH+=415). This residue was dissolved in 20 mL 1:1 trimethyl orthoformate: MeOH and the resulting solution were stirred for 30 minutes at room temperature. Yellow solids were precipitated from the orange solution. Desired product (0.6 g, 70% overall yield) was obtained after filtration.
Reaction SMILES: [Li]C(C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1.[Br:19][C:20]1[CH:21]=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCCCCCC.C1COCC1.O.CO>[Br:19][C:20]1[C:21]([C:16]2[S:15][C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=3)=[N:18][CH:17]=2)=[N:22][C:23]([Cl:26])=[N:24][CH:25]=1
Reactant: Fc1ccc(Nc2nccs2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2ncc(-c3nc(Cl)ncc3Br)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.1 mL (12 mmol) of a 1.5 M solution of tBuLi in heptane was added to a stirred solution of 1.1 g (5.5 mmol) of N-(4-fluorophenyl)thiazol-2-amine in 20 mL of THF at −20° C. The solution was stirred for 30 min and then cooled to −78° C. before 1.3 g (6.6 mmol) of 5-bromo-2-chloropyrimidine was added. The reaction solution was stirred for 30 min at −78° C., then quenched by addition of 0.2 mL of AcOH in 1 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10.4 g, 46 mmol) and 5 mL of MeOH were added and the reaction solution was warmed to 0° C. and stirred for 30 min, poured into 50 mL of a 0.5 M solution of sodium ascorbate, diluted with 200 mL of water and the crude product removed by filtration and washed repeatedly with water. The crude product was purified by flash chromatography eluting with a linear gradient of 10% EtOAc in hexane to 80% EtOAc in hexane to deliver the desired compound. MS (M+H)+ 387.