Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:49])=[C:29]([N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]2)[CH:30]=[C:31]([C:33]#[N:34])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2].O1CCOCC1>[Cl:49][C:28]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:20][CH2:19]3)[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[CH:32][C:31]([C:33]#[N:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
(I12C): 2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9, 0.912 g, 2.57 mmol), tert-butyl (1-(3-amino-2-chloro-5-cyanophenyl)piperidin-4-yl)carbamate (0.902 g, 2.57 mmol), Pd(OAc)2 (0.173 g, 0.771 mmol), DPPF (0.143 g, 0.257 mmol), Xantphos (0.149 g, 0.257 mmol), and cesium carbonate (1.675 g, 5.14 mmol) were combined in a round bottom flask and dioxane (17.14 ml) was added. The flask was evacuated and backfilled with nitrogen (3×), then heated at 100° C. for 1 h. The reaction mixture was filtered through Celite, rinsing with EtOAc. The organic layer was concentrated and the material was purified by column chromatography on the ISCO Companion (80 g, 0-100% EtOAc/Hex). tert-Butyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (1.14 g) was obtained as a yellow foam.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.[NH2:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37]>C(Cl)Cl>[C:1]([NH:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:33])([F:35])[F:34])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: C1COCCN1
Solvent: ClCCl
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Combine benzoyl chloride (19.3 mg, 0.137 mmol), PS-morpholine (109 mg, 0.272 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Filter the resin, wash with DCM and concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5 μm, 12 nm, 100×20 mm) to give 6-(2-benzoylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (65 mg, 57%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][SH:11])[C:5]([F:16])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:10][S:11][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:5]([F:16])=[CH:4][N:3]=1
Reactant: CC(C)(C)[C@@H](CS)Nc1nc(Cl)ncc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring suspension of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutane-1-thiol, 77a, (1.50 g, 5.69 mmol) and K2CO3 (2.36 g, 17.06 mmol) in acetone (15 mL) was added tert-butyl bromoacetate (1.26 mL, 8.53 mmol). The suspension was stirred at room temperature for 18 hours. The resulting solid was filtered, washed with acetone and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 1.6 g of the desired product as an off-white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H) 378.06.
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:31]([NH:33][C@@H:34]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C@H:35]([OH:49])[CH2:36][C@@:37]1([C:46]([NH2:48])=[O:47])[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])[CH2:15][C:16]1[N:20](C(OCC2C=CC=CC=2)=O)[CH:19]=[N:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>Cl>[N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:31]([NH:33][C@@H:34]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C@H:35]([OH:49])[CH2:36][C@@:37]1([C:46]([NH2:48])=[O:47])[CH2:41][CH2:40][CH2:39][N:38]1[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cncn1C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Agent: N#N
Agent: [Na+]
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(N)=O
Yield: 56.6 %

Procedure:
A solution of 30 mg of N2 -[3(S)-[[N,3-bis(benzyloxycarbonyl)-L-histidyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 6 ml of 2M hydrochloric acid was stirred at room temperature overnight. The mixture was neutralized by the addition of 2M sodium hydroxide solution and extracted with two 10 ml portions of dichloromethane. The combined extracts were dried over anhydrous sodium sulphate and evaporated. The crude product was triturated with diethyl ether to give 14 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-histidyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid of melting point 100° C. (decomposition); MS: m/e 604 [M]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[C:20]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1>O1CCOCC1>[C:26]([NH:25][C:20]1[C:19]([C:17]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:16]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)Nc1ncccc1C(=O)Nc1cnccc1Nc1cccc(F)c1F
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)Nc1ncccc1-c1nc2cnccc2n1-c1cccc(F)c1F
Temperature: 110 °C
Yield: 41.9 %

Procedure:
To a stirred solution of N-(4-(2,3-difluorophenylamino)pyridin-3-yl)-2-(tert-butylamino)pyridine-3-carboxamide (3.0 g, 7.55 mmol) in 1,4-dioxane (50 mL) was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent, 4.5 g, 11.3 mmol) at room temperature. The reaction mixture was heated at reflux (110° C.) for 10 hr. The reaction mixture was concentrated in vacuo and the resulting residue was taken in saturated aq. NaHCO3 solution (100 mL) and extracted with CHCl3 (200 mL). The organics were washed with water (3×100 mL), brine solution (1×100 mL), and dried (Na2SO4). Filtration and evaporation of solvent in vacuo, followed by silica gel chromatography (0.5% methanol/chloroform) gave N-tert-butyl-3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (1.2 g, 41.9% yield) as a light yellow solid; LC-MS: 380.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[N:17]=[C:16](Cl)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([N:8]1[N:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:35])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1nn(Cc2ccccc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)isoxazole (1.34 g, 6 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and Na2CO3 (1.59 g, 15 mmol) in toluene (25 mL), ethanol (12.5 mL) and water (12.5 mL) was degassed and heated to reflux with stirring for 18 h. After that time, the mixture was cooled to rt and diluted with ethyl acetate (80 mL). The organic phase was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The resulting semi-solid was triturated with hexanes to give a yellow solid. The product was purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate) followed by recrystallization from CHCl3/hexanes to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)phthalazin-1(2H)-one (0.39 g, 23%) as a white solid: mp 186-188° C.; 1H NMR (400 MHz, CDCl3) δ 8.55-8.53 (m, 1H), 7.83-7.76 (m, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.44-7.42 (m, 1H), 7.35-7.26 (m, 3H), 5.45 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].C(=O)([O-])O.[Na+].C(O)C.[C:18]([NH:26][C:27]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>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.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:18]([NH:26][C:27]1[CH:39]=[C:38]([C:6]2[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[CH:7]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccccc1
Reactant: Cc1ccc(I)cc1Cl
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1Cl
Temperature: 25 °C

Procedure:
0.031 mL of 2-chloro-4-Iodotoluene, 39 mg of sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of water and 11 mg of tetrakis(triphenylphosphine)palladium(0) were added to 1.6 mL of toluene solution containing 79 mg of tert-butyl 2-(benzamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate at room temperature, and the resulting mixture was heated to reflux for 8 hours. After the reaction mixture was cooled to room temperature, 11 mg of tetrakis(triphenylphosphine)palladium(9) was added and the resulting mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain tert-butyl 2-(benzamido)-4-(3-chloro-4-methylphenyl)benzoate as white solid.
Reaction SMILES: [CH3:1][C:2]([O:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][O:16]C1CCCCO1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C>[OH:16][CH2:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)OCCCC#CCOC1CCCCO1
Solvent: CCO
Product: CCOC(=O)C(C)(C)OCCCC#CCO
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Ethyl 2-methyl-2-[6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynyloxy]propionate (3.72 g) was dissolved in 37 ml of ethanol, and 15.372 mg of Amberlyst® was added thereto and the mixture was stirred for 1 hour at 55–60° C. After cooling, the mixture was filtrated and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1–3:1) to provide 1.98 g of the objective compound as pale yellow oil.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[N:16]=2)[CH2:8][CH2:7]1)(=O)=O.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CN(C)C=O>[C:30]([S:32][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)=[O:18])[N:16]=2)[CH2:8][CH2:7]1)(=[O:33])[CH3:31]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-methanesulfonyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (1.2 g, 2.72 mmol) (obtained as described in Reference Example 14(5)) in dimethylformamide (60 ml) was added potassium thioacetate (625 mg, 5.47 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (90° C.) for 3.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 4-acetylthio-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (769 mg, yield 88%) as a pale brown solid.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1>>[CH3:21][C:18]1[S:19][CH:20]=[C:16]([C:5]#[C:4][CH2:3][CH2:2][C:1]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[O:6])[N:17]=1
Reactant: C#CCCC(=O)Oc1ccccc1Cl
Reactant: Cc1nc(I)cs1
Product: Cc1nc(C#CCCC(=O)Oc2ccccc2Cl)cs1
Yield: 33.9 %

Procedure:
According to the protocol described in Example 237(B), the reaction between 2-chlorophenyl pent-4-ynoate (compound 160(A), 290 mg, 1.40 mmol) and 4-iodo-2-methylthiazole (315 mg, 1.40 mmol) afforded 145 mg of 2-chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate (Yield: 34%) as yellow-oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1cccc(C)c1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1c(C)cccc1C
Yield: 85.8 %

Procedure:
2-Bromo-m-xylene (186 mg, 1.01 mmol) reacted with 2-methylphenylboronic acid (164 mg, 1.21 mmol) using 2/4 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (640 mg, 3.00 mmol) in toluene at 100° C. to give the title compound (170 mg, 87%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.31-7.25 (m, 3H), 7.20-7.11 (m, 3H), 7.03 (m, 1H), 1.98 (s, 3H), 1.96 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].S(=O)(=O)(O)O>>[C:10]([N:6]1[CH2:7][CH:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:12])[CH3:11]
Reactant: CC1CNC(=O)NC1=O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N1CC(C)C(=O)NC1=O

Procedure:
In the manner described in I, 65 gm (0.5 mol) of 5-methyl-5,6-dihydrouracil and 817 gm (8 mols) of acetic acid anhydride and 2 ml of concentrated sulfuric acid were heated to boiling for ten hours with continuous distilling off of the acetic acid produced. The product, isolated after separating of the surplus acetic acid anhydride and purified by recrystallization from isopropanol, had a melting point of 111° C to 113° C. The analysis values were as follows:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Br
Product: COC(=O)c1ccc(OCc2ccccn2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E from methyl 4-hydroxybenzoate and 2-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:9][CH:8]=1.[O-]O.S(=O)(O)[O-:32].[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:9][CH:8]=1)=[O:32]
Reactant: CSCCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [O-]O
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound of Step C (650 mg, 1.55 mmol) was dissolved in 5 ml TFA and 3 ml DCM. At room temperature 79 mg (2.3 mmol) hydroperoxide 30% were added. This mixture was stirred at room temperature for 2 hours. Afterwards 10 ml 10% sodium bisulfite solution was added and stirring continued for 15 minutes. The solution was basified with 40% NaOH and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 0.35 g (50%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:32][C:27]1[CH:26]=[C:25]([C@@H:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: C1COCCN1
Product: Clc1ccc([C@H]2Cc3cnc(Nc4ccc(CCN5CCOCC5)cc4)nc3-c3ccccc32)cc1Cl
Yield: 45 %

Procedure:
This product was synthesized as described in general procedure 2 except (R)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and morpholine was used instead of piperidine to afford the title compound in 45% yield. M.p.=166-167° C. 1H NMR 400 MHz (CDCl3) δ 8.41 (dd, J=1.6 Hz, 7.6 Hz, 1H), 8.18 (s, 1H), 7.65-7.61 (m, 2H), 7.49-7.39 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.25-7.19 (m, 3H), 7.09 (s, 1H), 7.03-6.99 (m, 1H), 6.91 (dd, J=2.4 Hz, 8.4 Hz, 1H), 4.29-4.24 (m, 1H), 3.79-3.74 (m, 4H), 3.21 (dd, J=6.0 Hz, 15.6 Hz, 1H), 3.04 (dd, J=7.2 Hz, 15.6 Hz, 1H), 2.83-2.77 (m, 2H), 2.64-2.51 (m, 6H). LCMS m/e 531 (M+H).