Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:20]1([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[CH2:21][CH2:22]1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Boc-piperazine (7.2 g), 2,3-dichloro-5-methylpyridine (5 g), palladium (II) acetate (179 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (499 mg) and sodium tert-butoxide (4.1 g) was added toluene (30 mL), and the mixture was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). To a mixture of 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (30 g) and cyclopropylboronic acid (5.5 g) were added toluene (80 mL) and water (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the mixture was filtered to give the title compound (4.6 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>CN(C=O)C.CCOC(C)=O.O>[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[N:10]=1
Reactant: c1nc[nH]n1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cncc(-n2cncn2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1,2,4-triazole (276 mg, 4.0 mmol, 2.0 eq) in 1.5 mL of DMF was added carefully sodium hydride (60 wt. %. in mineral oil, 120 mg, 3.0 mmol, 3.0 eq) (caution: intensive gas development). The reaction mixture was stirred at room temperature for 45 min. 2,6-Dichloropyrazine (298 mg, 2.0 mmol, 1.0 eq) in 0.5 mL of DMF was added and the reaction mixture was heated at 95° C. for 60 min. The mixture was allowed to cool to room temperature and diluted with EtOAc (15 mL) and water (15 mL). The separated organic layer was concentrated under reduced pressure to afford crude material containing the title compound. The crude material was suspended in NMP (2 mL) and directly used in coupling reactions with phenols. ES/MS m/z 182.0, (MH+), Rt=1.68 min.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Zn](CC)CC.C(I)I.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27](=[CH2:33])[CH2:26]1)[C:20]#[N:21]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][C:24]=1[CH:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27]2([CH2:1][CH2:33]2)[CH2:26]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C1CC(c2ccc(C#N)cc2F)n2cncc21
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: N#Cc1ccc(C2CC3(CC3)c3cncn32)c(F)c1
Reaction time: 2 h

Procedure:
A solution of TFA (0.234 mL, 3 mmol) in 0.6 mL of dry CH2Cl2 is added dropwise to a solution of Et2Zn (1M in Hexanes, 3.06 mL, 3.06 mmol) at 0° C. The resulting suspension is subsequently treated with a solution of CH2I2 (0.246 mL, 3.06 mmol) in CH2Cl2 (0.4 mL). After 2 h at 0° C., a solution of 3-fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (333.8 mg, 1.392 mmol) in CH2Cl2 is added. After overnight, the reaction is quenched with saturated NaHCO3 solution, and extracted with CH2Cl2 (20 mL×4). The combined extracts are washed with brine, dried over anhydrous Na2SO4. After filtration and evaporation, the residue is purified by chromatography and yield 112 mg of oil. MS (ESI) m/z 254.2 (M+H). 1H NMR (400.3 MHz, CDCl3): δ 8.93 (s, 1H), 7.54-7.52 (m, 1H), 7.45 (d, J=8.00 Hz, 1H), 7.35 (m, 1H), 6.83 (s, 1H), 6.27 (brs, 1H), 3.22 (m, 1H), 2.61 (d, J=12 Hz, 1H), 1.33-1.19 (m, 2H), 1.16-1.14 (m, 1H), 0.90-0.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[C:8]([CH3:14])[C:7]=1C)=[O:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:26](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:17][C:2]([CH3:1])([CH3:16])[C:3]([O:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([O:13][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([CH3:26])[C:11]=1[CH3:12])=[O:4]
Reactant: ClCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)c(C)c(C)c1OC(=O)C(C)(C)C
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OC(=O)C(C)(C)C)c(C)c(C)c1OCc1ccccc1

Procedure:
A mixture of 43.5 g (184 mmol) of 2,2-dimethylpropanoic acid, 4-hydroxy-2,3,6-trimethylphenyl ester (Example A), 23.4 g (184 mmol) of benzyl chloride and 30.5 g (1.2×184 mmol) of anhydrous potassium carbonate in 500 mL of acetonitrile is stirred at reflux for 70 hours. The solid is removed and the reaction flask and solid are washed with fresh acetonitrile and the solvent removed on a rotary evaporator. The crude product amounts to 60.5 g which crystallizes on standing, mp 50°-53° C. Recrystallization from methanol in the presence of charcoal affords the title compound; mp 58°-59° C.
Reaction SMILES: [CH3:1][C:2](N(C1OC2C=CC=CC=2N=1)[C@H](C(O)=O)CC1C=CC(OCCCC(OCC)=O)=CC=1)([CH3:4])[CH3:3].[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][C@H:45]([C:66]([OH:68])=[O:67])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57](=[O:65])[NH:58][C:59]2[NH:60][CH2:61][CH2:62][CH2:63][N:64]=2)=[CH:49][CH:48]=1.NC1NCCCN=1>C(Cl)Cl>[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][C@H:45]([C:66]([O:68][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:67])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57](=[O:65])[NH:58][C:59]2[NH:60][CH2:61][CH2:62][CH2:63][N:64]=2)=[CH:51][CH:52]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@@H](C(=O)O)N(c2nc3ccccc3o2)C(C)(C)C)cc1
Reactant: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccccc3o2)C(=O)O)cc1)NC1=NCCCN1
Agent: NC1=NCCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2o1
Reaction time: 6 h
Yield: 96.8 %

Procedure:
The ester 6-1 (370 mg) is mixed with 2-amino-1,4,5,6-tetrahydropyrimidine (200 mg) in 5 ml of CH2Cl2 and agitation is carried out at ambient temperature for 6 hours. The reaction medium is then evaporated under reduced pressure and the dry extract obtained is purified by chromatography eluting with a CH2Cl2/MeOH/water/AcOH mixture 90/10/1/1. 200 mg of the expected product 6-2 is obtained.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH2:32]>CC(O)C>[CH:2]1([N:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[C:13](=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CC(C)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
90 g of D-glucose and 135 g of octadecylamine were heated at 50° C. in 1,000 ml of 2-propanol and 500 ml of water, with stirring, until a clear solution was formed. The solution was then left at room temperature overnight. The product was now filtered off with suction, washed with alcohol and ether, dried and, finally, recrystallized from ethanol/THF. 10 g of this N-octadecyl-β-D-glucopyranosylamine were suspended in 80 ml of THF and, after addition of 10 g of sodium carbonate, 7 g of oleoyl chloride in 10 ml of THF were added dropwise. After quantitative reaction (TLC in CH2Cl2 /CH3OH=13/1), the product was worked up as described in Example 12. Column purification with the eluting agent CH2Cl2 /CH3OH=13/1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1.CCN(C(C)C)C(C)C.[C:57](#[N:60])[CH:58]=[CH2:59]>CO>[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25]([N:24]=1)=[CH:26][C:27]1[CH2:28][N:29]([CH:36]3[CH2:37][CH2:38][N:39]([CH2:59][CH2:58][C:57]#[N:60])[CH2:40][CH2:41]3)[C:30](=[O:35])[C:31]=1[CH:32]=2
Reactant: C=CC#N
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCC#N)CC2)C4)c(C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of the TFA salt of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.061 mmol) in MeOH (2.4 mL) was added DIEA (600 μL, 3.4 mmol) at 0° C. under N2 resulting a mixture which was stirred under N2 at 0° C. for 20 min and followed by addition of acrylonitrile (197 μL, 3.0 mmol) via a syringe. The reaction mixture was stirred under N2 at 0° C. for 1 h and at the room temperature for 1 h and then evaporated. The residue was subjected to HPLC purification to afford the title compound in TFA salt form. 1H NMR (DMSO-d6) δ 1.99-2.13 (4H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.12 (m, 2H), 3.22 (m, 2H), 3.47 (m, 2H), 3.51-3.75 (4H), 4.01 (m, 2H), 4.13 (m, 1H), 4.34 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.96 (s, 1H), 7.36 (d, J=7 Hz, 1H), 7.59 (br s, 1H), 7.86 (br s, 1H), 11.13 (br s, 1H, NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 596.5 (MH+).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH2:23][OH:24].[B:25](OC)(OC)[O:26]C>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:15]1[C:14]2[CH2:23][O:24][B:25]([OH:26])[C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COB(OC)OC
Reactant: OCc1c(Br)cccc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB1OCc2c1cccc2C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a 2.5 M solution of n-BuLi in hexane (27.81 mL, 69.53 mmol) in dry THF (30 mL), cooled to −78° C. and under an Argon atmosphere was added a solution of (2-bromo-6-(trifluoromethyl)phenyl)methanol (CXXIX) (5.49 g, 23.16 mmol) in dry THF (30 mL) dropwise very slowly. The reaction mixture was stirred at −78° C. for 2 h before adding trimethyl borate (3.88 mL, 34.76 mmol). The reaction mixture was stirred at −78° C. for an additional 30 min, and then allowed to warm up slowly to room temperature and stirred overnight. The reaction was then cooled to 0° C. and slowly quenched with 2 M HCl and stirred for 2.5 h at room temperature. The reaction mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using (100:1 DCM/MeOH) to give 4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXX) as an orange oil (1.17 g, 5.79 mmol, 25% yield). ESIMS found for C8H6BF3O2 m/z 201.4 (M−H).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1>C(O)C>[NH:2]([C:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1)[NH2:3]
Reactant: NN
Reactant: CSc1nc(Cl)c2ncccc2n1
Solvent: O
Solvent: CCO
Product: CSc1nc(NN)c2ncccc2n1
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Hydrazine hydrate (13.0 mL (13.3 g, 237 mmol)) was added at ambient temperature with stirring to a mixture of 16.7 g (79 mmol) of 4-chloro-2-methylthiopyrido[3,2-d]pyrimidine in 200 mL of ethanol. There was a slight exotherm and the mixture thickened and then became more mobile again. After 30 min, the volatile components were removed by evaporation under reduced pressure. The residue was diluted with water and the solids were recovered by filtration, washed with ether, and dried to obtain 15.7 g of the title compound as a brown powder melting above 300° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[N:6][CH:5]=1.Cl.[CH2:16]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:30][CH:29]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (216 mg, 1.0 mmol) and 4-benzyloxyaniline hydrochloride (280 mg, 1.2 mmol) in MeOH (10 mL) was added iPr2NEt (0.35 mL, 2.0 mmol). The resulting mixture was stirred at rt overnight, a red solid precipitated from the mixture, which was collected by filtration. MS (ES, Pos.): m/z 380 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.94 (s, 3H), 5.10 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.38-7.46 (m, 5H), 7.50 (d, J=8.8 Hz, 2H), 9.01 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 10.2 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:30]2[CH2:29][CH2:28][N:27]([C:25]3[S:24][N:23]=[C:22]([C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)[N:26]=3)[CH2:32][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccs4)ns3)CC2)c1C
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 34.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (251 mg, 0.872 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 106 mg (31.1%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH:12]1[O:17][CH2:16][CH2:15]C[O:13]1>>[O:17]1[CH:16]=[CH:15][O:13][CH:12]1[CH2:11][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCC1OCCCO1
Product: CCOC(=O)CC(=O)CCC1OC=CO1

Procedure:
The title compound was synthesized from ethyl acetoacetate and 2-bromomethyl-1,3-dioxane, according to the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, (1971).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([N:6]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[C:7]1[S:8][C:9](C)=[C:10]([C:12](O)=[O:13])[N:11]=1)=[O:5].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([N:6]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:13])[N:11]=1)=[O:5]
Reactant: C1CCNC1
Reactant: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)ccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)N3CCCC3)cs2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
A mixture of 400 mg (0.85 mmol) 2-[(2,4-dichloro-benzoyl)-(4-chloro-3-methoxy-phenyl)-amino]-5-methyl-thiazole-4-carboxylic acid, 105 μL (1.27 mmol) pyrrolidine and 179 mg (1.10 mmol) 1,1′-carbonyldiimidazole in 12 mL dichloromethane was stirred for 16 h at room temperature. The mixture was poured onto 0.5 N hydrochloric acid and extracted with dichloromethane. Organic phases were pooled, washed with water and brine and dried with MgSO4. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography (n-heptane/ethyl acetate 1:1) to yield 270 mg (60%) of the title compound as colorless solid. MS (m/e): 524.1, 526.1 (MH+)
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1.O.[NH2:19][NH2:20]>CO>[NH:4]1[C:5]([C:6]2[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([NH:19][NH2:20])=[O:13])=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: NN
Reactant: COC(=O)COc1ccc(-c2nn[nH]n2)cc1
Solvent: CO
Solvent: O
Product: NNC(=O)COc1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a suspension of methyl [4-(2H-tetrazol-5-yl)phenoxy]acetate (1.10 g, 4.06 mmol) in MeOH (30 mL) was added hydrazine hydrate (2.0 mL). After stirring for 90 min at rt, the reaction mixture was evaporated off. The residue was taken up with MeOH (10 mL) and a white solid precipitated out. Filtration, washing with MeOH (2×3 mL) and drying under vacuo at 70° C. for 16 hrs gave 741 mg of the title compound (78%) as a white solid in 99.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][OH:11].[H-].[Na+].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][O:11][CH2:18][CH2:17][C:16]([NH2:20])=[O:19]
Reactant: C=CC(N)=O
Reactant: CN(C)CCOCCN(C)CCO
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOCCN(C)CCOCCC(N)=O

Procedure:
A 50 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 19.0 g of 2-{[2-(2-dimethylaminoethoxy)ethyl]methylamino}ethanol. Sodium hydride, 0.03 g, was then added carefully to the 2-{[2-(2-dimethylaminoethoxy)ethyl]methylamino}ethanol solution with stirring. The mixture was stirred at a constant rate for two minutes before 7.10 g of acrylamide was added. After the addition of acrylamide, the reaction mixture was stirred at 55° C. for 6 hours. The mixture was cooled to ambient temperature and neutralized with 0.80 g of concentrated sulfuric acid. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application without further purification. Quantitative 1H NMR showed that the product was 94% pure.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: C1CCNC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and pyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27](I)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([Br:25])=[CH:23][N:24]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCI
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[(4-{2-[(5-Bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.27 g) synthesized in Example 162-1 and heptyl iodide (1.77 g) were dissolved in N,N-dimethylformamide (36 mL), potassium tert-butoxide (0.80 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.80 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:58]=[CH:57][C:53]([CH:54]([OH:56])[CH3:55])=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][C:50]([F:49])=[CH:51][CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 47.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluoro-α-methylbenzyl alcohol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 47%).