Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[NH:6]1[C:15](=[O:16])[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[NH:9][C:7]1=[S:8].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35]>O>[OH:16][C:15]1[N:6]=[C:7]([S:8][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([N+:34]([O-:36])=[O:35])[CH:28]=2)[N:9]=[C:10]2[C:14]=1[N:13]=[CH:12][NH:11]2
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSc2nc(O)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A DMF (100 ml) solution of 2-thioxanthine (7.75 g, 46 mmol), triethylamine (8.0 ml, 60 mmol), 4-methoxy-3-nitrobenzyl bromide (12.48 g, 51 mmol) was heated and stirred at 100° C. for 3 hours. Water was added to the reaction solution, the precipitated crystals were collected by filtration and washed sequentially with water and ether to obtain 14.67 g (95% yield) of 6-hydroxy-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:41]=[C:40]([I:42])[CH:39]=[CH:38][C:24]=1[CH2:25][N:26]1[C:30]2=[CH:31][N:32]=[CH:33][CH:34]=[C:29]2[CH:28]=[C:27]1[C:35]([O-])=[O:36].[Na+].[CH3:44][C:45]1([CH3:53])[O:49][C@@H:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.CCN(C(C)C)C(C)C>C1COCC1.ClCCl.C(OCC)(=O)C>[CH3:44][C:45]1([CH3:53])[O:49][C@@H:48]([CH2:50][O:51][NH:52][C:35]([C:27]2[N:26]([CH2:25][C:24]3[CH:38]=[CH:39][C:40]([I:42])=[CH:41][C:23]=3[F:22])[C:30]3=[CH:31][N:32]=[CH:33][CH:34]=[C:29]3[CH:28]=2)=[O:36])[CH2:47][O:46]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C([O-])c1cc2ccncc2n1Cc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](CONC(=O)c2cc3ccncc3n2Cc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
EDCI (259 mg, 1.08 mmol) and HOBt (204 mg, 1.51 mmol) were added to a suspension of sodium 1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (494 mg, 1.08 mmol) in THF (7 ml). The suspension was warmed gently for 1 minute before the addition of a solution of O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (222 mg, 1.51 mmol) in THF (3 ml) followed by DIPEA (0.19 ml, 1.10 mmol). The reaction mixture was stirred at room temperature for 18 hours, poured into ethyl acetate (60 ml) and washed sequentially with 0.1M HCl (10 ml), saturated NaHCO3 solution (10 ml) and brine (10 ml). The organic layer was isolated and dried over magnesium sulphate, then concentrated in vacuo to provide a residue. Trituration of the residue in dichloromethane afforded the title compound as a pale cream solid (0.433 g, 76%). LCMS (method B): RT=2.32 min, (M+H)+=524, M+H+=526.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.Br[C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH3:21])([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)[CH3:20]
Reactant: Oc1cccc(-c2cccnc2)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Temperature: 93 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
A mixture of 3-pyridin-3-yl-phenol (0.86 g, 5.0 mmol), methyl 2-bromoisobutyrate (3.60 g, 20.0 mmol), and K2CO3 (2.76 g, 20.0 mmol) in anhydrous DMF (10 mL) was heated at 93° C. under nitrogen for 3 h. After cooling, brine (40 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The separated organic layer was washed with brine, filtered, and concentrated. The oil residue was taken up in 10 mL of 3 M HCl, stirred for 10 min, diluted with brine (10 mL), and extracted with ethyl acetate (2×30 mL). The separated aqueous layer was cooled in ice/water bath, adjusted to pH 10 with solid Na2CO3, and extracted with ethyl acetate (2×40 mL). The organic extract was dried over sodium sulfate and concentrated to afford 1.09 g (80%) of 2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid methyl ester as a yellow oil: 1H NMR (CDCl3) δ 1.62 (s, 6H), 3.79 (s, 3H), 6.82 (dd, 1H), 7.08 (s, 1H), 7.20 (d, 1H), 7.38 (m, 2H), 7.81 (d, 1H), 8.59 (d, 1H), 8.80 (s, 1H); MS m/z (relative intensity) 271 (M+, 20), 212 (30), 171 (100).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N:14]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCN2CCCCC2)cc1
Yield: 118.7 %

Procedure:
A solution of 1-(2-chloroethoxy)-4-nitrobenzene (2.01 g, 0.01 mol), piperidine (2.55 g, 0.03 mol), and toluene (10 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate evaporated to give 2.97 g of 1-[2-(1-piperidinyl)ethoxy]4-nitrobenzene as an orange oil, MS M+ (m/e) 251.18. This material (1.25 g, 0.004 mol) was hydrogenated in ethanol (25 mL) in the presence of 10% Pd—C catalyst at 40 psig and 25° C. overnight. Filtration and evaporation of the reaction mixture gave 0.95 g of 4-[2-(1-piperidinyl)ethoxy]aniline as a light brown oil, MS M+ (m/e) 221.24. A solution of this oil (0.220 g, 1.0 mmol), 3-methyl-5,8-dimethoxy-2-tetralone (6, 0.206, 0.94 mmol), and 1,2-dichloroethane (3.5 mL) was treated with sodium triacetoxyborohydride (0.300 g, 1.4 mmol) and acetic acid (0.060 g, 1.0 mmol) and the resulting mixture was stirred overnight at 25° C. The reaction was treated with 3N sodium hydroxide solution with vigorous stirring. The organic layer was separated, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered and evaporated to a red oil. This material was purified by C-18 reverse phase high pressure liquid chromatography affording compound 60 as a pink solid. 1H NMR (300 MHz, CDCl3): δ 7.10-7.22 (m, 2H), 6.52-6.82 (m, 4H), 4.25-4.33 (m, 2H), 3.60-3.80 (m, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.48-3.38 (m, 2H), 2.80-3.05 (m, 4H), 1.80-2.10 (m, 4H), 1.10-1.50 (m, 3H), 1.00 (d, 3H). MS M+ (m/e) 425.38.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([O:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([CH:25]([OH:35])[CH2:26][C:27]3[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=3[Cl:34])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl.O>[CH:11]1([O:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([C:25](=[O:35])[CH2:26][C:27]3[C:28]([Cl:34])=[CH:29][N:30]=[CH:31][C:32]=3[Cl:33])[CH:18]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1cnc(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1cnc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
Oxalyl chloride (50 mL) in dry dichloromethane (1.5 mL) is cooled to −30° C. under a nitrogen atmosphere. Dimethyl sulphoxide (80 mL) is added, the mixture stirred for 10 minutes then a solution of (±)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanol (210 mg) in dichloromethane (2.5 mL) is added and the mixture stirred for 3 hours. Triethylamine (0.2 mL) is added and the mixture is allowed to warm to room temperature. After pouring into water the organic phase is extracted into dichloromethane, the extracts washed sequentially with 1% aqueous sulphuric acid, water, saturated aqueous sodium bicarbonate and water. The extracts are dried (MgSO4) and evaporated to give a solid. The solid is triturated with pentane, collected and dried to give 1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone (60 mg), as an off-white solid, m.p. 132° C. [Elemental analysis:—C, 56.80; H, 4.92; N, 7.10% calculated:—C, 56.71; H, 4.78; N, 7.35%].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CCCP(=O)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: NCc1ccccc1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)NCc3ccccc3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 4.5 mL CH2Cl2 at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.131 mL, 0.22 mmol). After 5 min at rt, benzyl amine (0.023 mL, 0.21 mmol) was added and the reaction stirred at rt for 23 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with aqueous NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and evaporated to a solid. The solid was chromatographed eluting with CHCl3/EtOAc plus 5% MeOH and then triturated with acetone/hexane to give the title compound as a light beige solid (20 mg, 28%). 1H NMR (Acetone-d6) δ: 8.39 (br. s., 1H), 8.12 (s, 1H), 7.58 (br. s., 1H), 7.27-7.38 (m, 5H), 7.16-7.26 (m, 2H), 4.59 (d, J=5.6 Hz, 2H), 4.30 (s, 2H), 3.66 (t, J=5.3 Hz, 2H), 2.82 (t, J=5.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.C(N(CC)CC)C.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:7][CH2:6][CH:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCC1CC(F)(F)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of (3,3-difluorocyclobutyl)methanol (500 mg, 4.09 mmol, 1.00 equiv), triethylamine (662.6 mg, 6.55 mmol, 1.60 equiv), and 4-dimethylaminopyridine (750 mg, 6.14 mmol, 1.50 equiv) in CH2Cl2 (5 mL) under argon at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.01 g, 5.30 mmol, 1.30 equiv) in portions. The resulting mixture was stirred overnight at ambient temperature. The mixture was then diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified using flash column chromatography (silica gel, EtOAc/Hexanes (1:5)) to yield 1.1 g (97%) of a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ ppm 7.77 (d, J=7.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.03 (d, J=6.5 Hz, 2H), 2.75-2.50 (m, 2H), 2.50-2.36 (m, 4H), 2.36-2.08 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.O.[NH2:29][NH2:30]>ClCCl>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=[C:2]([NH:29][NH2:30])[C:11]1=[O:12]
Reactant: COc1ccc(Cn2c(=O)c(Cl)nc3ccc4ccccc4c32)c(OC)c1
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2c(=O)c(NN)nc3ccc4ccccc4c32)c(OC)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 3-chloro-1-(2,4-dimethoxybenzyl)benzo[f]quinoxalin-2(1H)-one (900 mg, 2.4 mmol) and hydrazine hydrate (250 μl, 5.1 mmol) in dichloromethane (70 ml) was stirred at room temperature. After 48 h the mixture was evaporated to dryness. The residue was triturated with ice/water, filtered and dried in vacuo to give 800 mg (85%) of the title compound. M.p. 182°-183° C., 1H-NMR (CDCl3): δ 3.80 (s, 3H), 3.85 (s, 3H), 4,15 (br. s, 2H), 5.58 (s, 2H), 6.45 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H), 7.40 (m, 3H), 7.70 (s, 2H), 7.85 (dd, 1H), 8.10 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:37]2[N:38](C(OC(C)(C)C)=O)[CH:39]=[CH:40][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:37]2[NH:38][CH:39]=[CH:40][CH:41]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2ccc[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 28.1, 100 mg, 0.217 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (127 mg, 0.434 mmol), Pd(PPh3)2Cl2 (15.22 mg, 0.022 mmol), Na2CO3 (92 mg, 0.867 mmol), DME (920 μL), water (263 μL) and EtOH (131 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 90 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 40% to 100% EtOAc) followed by preparative SFC (Column NH2, from 25% to 30% in 10 min) to yield the title compound as a grey solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=448.1 [M+H]+, m/z=446.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (d, J=11.00 Hz, 2H) 3.28-3.34 (m, 6H) 3.86 (br. s, 2H) 4.97 (d, J=3.42 Hz, 2H) 6.03-6.07 (m, 1H) 6.07-6.12 (m, 1H) 6.75-6.77 (m, 1H) 6.78 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 2H) 7.82 (dd, J=8.80, 2.45 Hz, 1H) 7.85 (d, J=2.20 Hz, 1H) 7.86-7.91 (m, 2H) 10.07 (s, 1H) 10.97 (d, J=1.71 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.CC1(C)C(C)(C)OB([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(C)cc2)c1C
Temperature: 110 °C
Yield: 74.9 %

Procedure:
A mixture of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (220 mg, 0.578 mmol), 4,4,5,5-tetramethyl-2-(4-methyl-benzyl)-1,3,2-dioxaborolane (402 mg, 1.731 mmol), palladium(II) acetate (17 mg, 0.0757 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (53 mg, 0.129 mmol), potassium phosphate (246 mg, 1.159 mmol), toluene (5 mL) and water (0.5 mL) was heated at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with brine (25 mL). The organic phase was dried over MgSO4, filtered and concentrated. Silica gel chromatography (93:7 hexanes-ethyl acetate) gave 145.7 mg (74.9%) of [6-fluoro-3-methyl-4-(4-methyl-benzyl)-naphthalen-2-yl]-acetic acid methyl ester as a colorless oil which solidified on standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.8, 6.2 Hz, 1 H), 7.75 (s, 1 H), 7.63 (dd, J=12.4, 2.1 Hz, 1 H), 7.33 (td, J=8.8, 2.1 Hz, 1 H), 7.03 (d, J=7.8 Hz, 2 H), 6.92 (d, J=7.8 Hz, 2 H), 4.40 (s, 2 H), 3.93 (s, 2 H), 3.64 (s, 3 H), 2.30 (s, 3 H), 2.21 (s, 3 H).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=2)[CH2:28][N:29]([CH3:41])[C:30](=[O:40])[CH2:31][NH:32]C(=O)OC(C)(C)C)=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:2].[ClH:18].[Cl:1][C:11]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:12]1[CH2:17][CH2:16][N:15]([C:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:44]=[CH:43][CH:42]=[C:27]([CH2:28][N:29]([C:30](=[O:40])[CH2:31][NH2:32])[CH3:41])[CH:26]=3)=[CH:23][N:24]=2)[CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1)C(=O)CN
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3 chloro-4-(piperazin-1-yl)benzoic acid hydrochloride (142 mg) was suspended in DMF (3 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (190 mg) and DIPEA (371 mg) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino)methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid dihydrochloride (72 mg).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13].[H-].[Na+].Br[CH2:18][C:19]1[CH:20]=[C:21]([Br:27])[CH:22]=[CH:23][C:24]=1[CH2:25]Br.[Cl-].[NH4+]>CN(C)C=O>[CH2:18]([C:19]1[CH:20]=[C:21]([Br:27])[CH:22]=[CH:23][C:24]=1[CH2:25][O:14][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13])[O:14][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: COCCOCCOCCOCCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCc1ccc(Br)cc1COCCOCCOCCOCCOC
Yield: 68.9 %

Procedure:
Next, 3.74 g (18.0 mmol) of 3,6,9,12-tetraoxa-1-tridecanol was added to a solution of 1.92 g (48.0 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (65 ml) in the atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, to the reaction mixture was added 2.57 g (7.49 mmol) of 3,4-bis(bromomethyl)-1-bromobenzene, and the mixture was reacted at room temperature for 19 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 3.08 g (5.16 mmol) of 3,4-bis(2,5,8,11,14-pentaoxapentadecanyl)-1-bromobenzene.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[NH:20]1[C:28]2[N:23]3[C:24](=[N:29][CH:30]=[C:22]3[C:21]1=[O:31])[CH:25]=[CH:26][CH:27]=2.C1CCN2C(=NCCC2)CC1>CN(C=O)C.O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:20]2[C:28]3[N:23]4[C:24](=[N:29][CH:30]=[C:22]4[C:21]2=[O:31])[CH:25]=[CH:26][CH:27]=3)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=c1[nH]c2cccc3ncc1n32
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)c3cnc4cccc2n43)CC1
Yield: 43.5 %

Procedure:
A mixture containing 5.68 g (20.0 mM) of (1-tert-butoxycarbonylpiperidin-4-ylmethyl) methanesulfonate, 4.35 g (20.0 mM) of 1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one.2NaCl, and 3.58 ml (24.0 mM) of DBU in 50 ml of DMF was heated at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured in 50 ml of iced water and extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of purified water twice and, then, with 50 ml of saturated aqueous NaCl solution and dried over Na2SO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethanol=10:1) to provide 3.00 g (yield 42.1%) of the title compound as a brown amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.[CH3:24][C:25]([CH3:41])([CH2:30][CH2:31][CH2:32][C:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26]([O:28][CH3:29])=[O:27].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.CO>[CH3:24][C:25]([CH3:41])([CH2:30][CH2:31][CH2:32]/[C:33](=[N:21]\[O:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)/[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: COC(=O)C(C)(C)CCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)(C)CCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 47 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (467 mg), methyl 2,2-dimethyl-6-oxo-6-phenylhexanoate (340 mg), acetic acid (0.259 ml), sodium acetate (248 mg) and methanol (15 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (348 mg, yield 47%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.