Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5](=[O:6])[CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].CCCCCC.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>O=P(N(C)C)(N(C)C)N(C)C>[OH:6][C:5]1[S:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]=1[C:25](=[O:26])[CH2:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: O=C1Cc2ccccc2S1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Cc1cccs1)c1c(O)sc2ccccc12

Procedure:
In a sulfonating flask under a nitrogen atmosphere, 15 g of benzo[b]thiophene-2(3H)-one (100 mmol) are dissolved in 150 ml of distilled hexametapol. The light-yellow solution is cooled to 5°. 8.9 g of a sodium hydride suspension (55%) that has been de-oiled with n-hexane are then added in portions while stirring. The resulting suspension is stirred for 15 minutes at 20°, during which time the evolution of gas is observed. The suspension is then cooled to -10°and 17.65 g of 2-(2-thienyl)-acetic acid chloride are added, the internal temperature being maintained at below 0°. After the cooling has been removed, the mixture is stirred for 1 hour. The reaction mixture is poured onto 2 liters of ice-water and 60 ml of 2N hydrochloric acid, and then 500 ml of toluene are added. The separated organic phase is extractedtwice with water and then three times using 200 ml of 5% soda solution eachtime. The alkaline phase is filtered and poured onto ice and 2N hydrochloric acid, and the crystals that are formed are filtered off and dried. Chromatography over silica gel and recrystallisation from methanol yield 2-hydroxy-3-[2-(2-thienyl)-acetyl]-benzo[b]thiophene, ##STR7##
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:3]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH2:3]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CC[C@H](N)C2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 89.3 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-[(3S)-3-aminopyrrolidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (237a) (150 mg, 0.59 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (103 mg, 0.59 mmol), WSC hydrochloride (338 mg, 1.76 mmol), 1-hydroxybenzotriazole (79 mg, 0.59 mmol) and N-methylmorpholine (0.13 mL, 1.17 mmol), to obtain 217 mg of the title compound as a white solid (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(#N)C>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
An 0.4 g. portion of 5-chloro-2-aminopyridine was dissolved in 20 ml. of acetonitrile and reacted with 0.7 g. of 2-chloro-6-fluorobenzoyl isocyanate as described in Example 1. The yield was 0.65 g. of the product named above, m.p. 210°-215° C. Elemental analysis gave the following results:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[C:28]([S:32]([CH2:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:40][C:41]=1[Cl:42])(=[O:34])=[O:33])([CH3:31])([CH3:30])[CH3:29].[F-].[Cs+]>COCCOC.C(O)C>[C:28]([S:32]([CH2:35][C:36]1[CH:37]=[C:38]([C:12]2[CH:11]=[CH:10][C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:39]=[CH:40][C:41]=1[Cl:42])(=[O:34])=[O:33])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: CC1(C)OB(c2ccc(Cl)c(CS(=O)(=O)C(C)(C)C)c2)OC1(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2ccc(Cl)c(CS(=O)(=O)C(C)(C)C)c2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.1 g, 2.65 mmol) was dissolved in 1,2-dimethoxyethane (15.7 ml) and ethanol (1.5 ml). 2-{3-[(tert-butylsulfonyl)methyl]-4-chlorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.09 g, 2.92 mmol) was added and argon was bubbled in the solution for 10 minutes. Cesium fluoride (0.89 g, 5.84 mmol) and palladium tetrakistriphenylphosphine (0.153 g, 0.13 mmol) were: added for 2.5 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate and water. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) giving 0.53 g (39%) of the desired product.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:64])[N:61]([CH3:63])[CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:64])[N:61]([CH3:62])[CH3:63])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(=O)N(C)C)N(C(=O)OCC=C)C1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(=O)N(C)C)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 44.5 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (129 mg, 0.26 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (110 mg, 0.26 mmol) and N,N-diisopropylethylamine (45 μl, 0.26 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (78 mg, yield: 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:18]([CH3:20])[CH3:19])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
A reaction mixture solution prepared by suspending 2.18 g of 4-bromo-2-nitrophenol and 2.07 g of potassium carbonate in 40 mL of dimethylformamide and adding 2.04 g of isopropyl iodide was heated under stirring at 110° C. for 14 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 2.08 g of 4-bromo-2-nitro-1-(propan-2-yloxy)benzene. (2) A suspension was prepared by adding 1.05 g of potassium hydrogen carbonate, 22 mg of palladium chloride (II) and 102 mg of a copper bromide (I) dimethylsulfide complex to 2.08 g of 4-bromo-2-nitro-1-(propan-2-yloxy)benzene obtained above, followed by suspending the mixture in 15 mL of toluene. Subsequently, a reaction mixture solution prepared by adding 1.02 g of ethyl 4-methyl-1,3-thiazole-5-carboxylate, 46.2 μL of isobutyric acid and 114 mg of di-t-butylcyclohexylphosphine to the suspension was heated at 120° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was celite-filtered to remove insoluble matter, water was added to the filtrate, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 1.38 g of ethyl 4-methyl-2-[3-nitro-4-(propan-2-yloxy)phenyl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH2:21][NH:22][CH3:23])[S:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>>[C:24]([CH2:23][NH:22][CH2:21][C:19]1[S:18][CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=2)[CH:20]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Cl
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Product: CCCC(=O)CNCc1cc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)cs1
Yield: 99.1 %

Procedure:
In a manner similar to that of Example 16(e), starting with 0.1 g (0.3 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate and 40 μl (0.33 mmol) of butanoyl chloride, 0.12 g (75%) of methyl 3-(4-{5-[(butyrylmethylamino)methyl]thiophen-3-yl}phenyl)-2(S)-ethoxypropanoate is obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].N1CCCC1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH2:13][C:23]([CH2:22][CH2:21][C:20]([O:27][CH2:28][CH3:29])=[O:26])([CH3:25])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2=O

Procedure:
A solution of 58.0 g (0.299 mole) of 2,4-dihydroxy-3-propylacetophenone and 29.5 ml (0.36 mole) of pyrrolidine in 250 ml of toluene was heated to reflux for three hours under a Dean-Stark trap. After cooling the mixture, 68.2 ml (0.48 mole) of ethyl levulinate was added and the mixture was refluxed for two hours. An additional 10 ml (0.12 mole) of pyrrolidine was added and the mixture was refluxed overnight under a Dean-Stark trap.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:22]([CH3:25])([CH3:24])[OH:23])[CH:5]=[C:6]([O:20][CH3:21])[C:7]=1[O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[N:12]=[C:11]([CH3:19])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][CH2:33][CH2:34][CH:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:22]([CH3:25])([CH3:24])[OH:23])[CH:5]=[C:6]([O:20][CH3:21])[C:7]=1[O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:39][CH:35]([CH2:36][CH2:37][CH3:38])[CH2:34][CH2:33][CH3:32])[N:12]=[C:11]([CH3:19])[N:10]=1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: CCCC(N)CCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[[6-chloro-2-methyl-5-nitro-4-pyrimidinyl]oxy]benzenemethanol (1.88 g) in anhydrous 1,4-dioxane (50 mL) with 0.50 g of potassium carbonate, 4-heptylamine (1.00 mL) was added and the solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in water and extracted with methylene chloride. The extracts were combined and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane to yield the title compound, mp 138° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C1(C)C=CC(S(O[CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])(=O)=O)=CC=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COc1ccccc1CCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 2.80 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 3.71 g of 2-[2-(2-methoxyphenyl)ethoxy]ethyl toluene-4-sulphonate (Example 45b) are reacted. The title compound is obtained as a colourless oil. Rf=0.47 (1:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@@H:12]3[CH2:17][N:16]4[CH2:18][CH2:19][N:20](C(OCC5C=CC=CC=5)=O)[CH2:21][C@H:15]4[CH2:14][N:13]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:9]=2)[C:4](=[O:39])[O:3]1>CO.[Pd]>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@@H:12]3[CH2:17][N:16]4[CH2:18][CH2:19][NH:20][CH2:21][C@H:15]4[CH2:14][N:13]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:9]=2)[C:4](=[O:39])[O:3]1
Reactant: C[C@@H]1Cc2cc([C@@H]3CN4CCN(C(=O)OCc5ccccc5)C[C@H]4CN3C(=O)OC(C)(C)C)ccc2C(=O)O1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1Cc2cc([C@@H]3CN4CCNC[C@H]4CN3C(=O)OC(C)(C)C)ccc2C(=O)O1
Reaction time: 8 h

Procedure:
To the solution of (3R,9aS)-8-benzyl 2-tert-butyl 3-((R)-3-methyl-1-oxoisochroman-6-yl)tetrahydro-1H-pyrazino[1,2-a]pyrazine-2,8(9H,9aH)-dicarboxylate (0.590 g, 1.10 mmol) in methanol (20 mL) was added palladium on carbon (10%, 0.117 g, 0.110 mmol) and the mixture was subjected to hydrogenation at rt overnight. After filtration the filtrate was concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:36][C:35]1[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 125 °C
Yield: 90.4 %

Procedure:
To a mixture of 1-(3-(7-chloroimidazo[1,2-a]pyridin-3-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea (20 mg, 0.052 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 mg, 0.066 mmol) and cesium carbonate (51 mg, 0.156 mmol) in THF/H2O mixture (2/1, 0.75 ml) was added Pd(PtBu3)2 (3 mg, 0.005 mmol). The vial was degassed for 5 minutes then capped and heated to 125° C. for 20 minutes in a microwave. After cooling to ambient temperature, the reaction mixture was filtered through a celite pad and purified via flash chromatography (0-10% MeOH/DCM gradient containing 10% NH4OH) to yield the title compound (20 mg, 90% yield). MS (ES+) C22H18F3N5O requires: 425. found: 426 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH:12]3[C@H:14]([OH:15])[CH:9]2[CH2:10][CH2:11]3)=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:15][C@H:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[C@@:8]([OH:16])([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:13]3)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc([C@@]2(O)CC3CCC2[C@H]3O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc([C@@]2(O)CC3CCC2[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 36 h

Procedure:
A 50 mL round-bottomed flask, equipped with a drying tube, was charged with dry pyridine (5 mL), [2R*,7S*]-2-(4-methylphenyl)bicyclo[2.2.1]heptane-2,7-diol (0.8 g, 3.7 mmole, prepared as in Part C above) and p-toluenesulfonyl chloride (0.74 g, 3.88 mmole), and the resultant reaction mixture allowed to stand for 36 hours at ambient temperature. Saturated sodium bicarbonate solution (25 mL) was then added, and the resultant mixture extracted twice with 25 mL aliquots of diethyl ether. The ether extracts were combined, washed with distilled water and dried over anhydrous sodium sulfate, then the ether was removed on a rotary evaporator. The pale yellow solid residue thus produced was purified by flash column chromatography on silica gel using a 1:1 v/v diethyl ether/hexane mixture as eluant, then recrystallized from diethyl ether/pentane to give the desired product as a white crystalline solid, yield 1.0 g, 74% based upon the diol starting material. This product decomposed at 68° C. before melting. The product was characterized as follows:
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]2[CH:14]=[N:15][C:16](Cl)=[N:17][C:5]1=2)[CH:2]=[CH2:3].[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:25])=[CH:22][C:21]=3[O:36][CH3:37])=[N:17][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: C=CCN1CC(C)C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Yield: 50.1 %

Procedure:
A solution of 0.050 g (0.00019 mole) of (rac)-9-allyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-65), 0.049 g (0.00019 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00025 mole) of p-toluene-sulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25) to give 0.047 g of (rac)-4-(9-allyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-65) as white solid. HRMS (ES+) m/z Calcd for C26H35N7O3+H [(M+H)+]: 494.2874. Found: 494.2878.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1csc(CCC2(C(C)C)CC(O)=CC(=O)O2)n1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(CCC2(C(C)C)CC(O)=C(Sc3cc(C)c(CO)cc3C(C)(C)C)C(=O)O2)n1

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-6; 0.33 g, 1.2 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.51 g, 1.4 mmol), potassium carbonate (0.48 g, 3.5 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 98-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([OH:26])[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[O:21][CH:22]=[CH:23][CH:24]=4)=[C:14]3[C:13](=[O:25])[O:12]2)[N:4]=1.[CH3:27]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[C:13]([O:12][CH3:27])=[O:25])=[O:26])[N:4]=1
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccco4)ccnc32)n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(-c2ccco2)ccnc1C(=O)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
2.1 g of 7-(4,6-dimethoxypyrimidin-2-yl)-4-(2-furyl)-7-hydroxyfuro[3,4-b]pyridin-5(7H)one was weighed out, and 50 ml of N,N-dimethylformamide and 0.82 g of potassium carbonate were added thereto. The mixture was stirred at room temperature. 0.8 g of methyl iodide was added thereto dropwise, and the mixture was stirred at room temperature overnight, then poured into water and extracted 200 ml of ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/3) to obtain 1.1 g (yield 50.7%) of the desired compound as brown crystals. m.p.: 135°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 62 %

Procedure:
Using 5-chlorosalicylic acid and 3-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH2:25](I)[CH3:26]>O>[CH2:25]([N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)[C:15](=[O:17])[CH3:16])[CH3:26]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1 h

Procedure:
A mixture of 4.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide, 0.85 g of sodium hydride (50% in oil) and 300 ml of dry dimethylformamide, under argon, was stirred for 1 hour then 1.42 ml of ethyl iodide was added. After stirring for 2.5 hours, 0.5 equivalent of sodium hydride and 1.1 equivalent of ethyl iodide were added. This mixture was stirred overnight, poured into 1 liter of water and extracted with five 100 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo, giving 3.6 g of the desired compound as tan crystals, mp 105°-110° C.