Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(=O)OCC
Yield: 80 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10 gm, 0.3 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (0.7 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 90 mg (80%) of 2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-fluorobenzofuran, mp. 85°-88° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.[K]>CN(C)C=O>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C@H:7]2[CH2:6][N:49]2[C:45](=[O:55])[C:46]3=[CH:54][CH:53]=[CH:52][CH:51]=[C:47]3[C:48]2=[O:50])=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 65.8 %

Procedure:
A solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (4.39 g: 6.93 mmole) and potassium phthalimide (2.57 g: 2 eq.) in dimethylformamide (30 ml) is stirred at 70° C. for 6 hours. The reaction mixture is poured into ice water and the precipitate is filtered off. The precipitate is dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-tritylthiopyrrolidine (3.12 g). Yield: 64.3%.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 6.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 339 mg of 4-methylindoline hydrochloride, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 241 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 22 mg of 2-[2-(4-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a fuchsia crystalline powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[CH3:14])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 1-boc-piperazine (8.19 g, 43.9 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) was added 3,3-dimethylbutyraldehyde (4.0 g, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.27 g, 51.9 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with saturated NaHCO3, water and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% EtOAc) to yield the title compound (9.1 g, 84%).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH2:19]([O:21][C:22]1[C:23]([C:34](N(OC)C)=[O:35])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:26]=1)[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22]1[C:23]([C:34]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:35])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:26]=1)[CH3:20]
Reactant: FC(F)(F)c1cc(I)ccn1
Reactant: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)N(C)OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)c1ccnc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 8.5 mL, 11.0 mmol) was added to a solution of 4-iodo-2-(trifluoromethyl)pyridine (3.0 g, 11.0 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. After 10 minutes, the solution was stirred at 23° C. for 35 min. The dark reddish brown solution was then cooled to −78° C. A solution of 5-ethoxy-2-(4-fluorophenyl)-N-methoxy-N-methyl-2H-1,2,3-triazole-4-carboxamide (i.e. the product of Step B, 2.5 g, 8.5 mmol) in tetrahydrofuran (25 mL) was added. The solution was stirred at 23° C. for 22 h. The reaction was quenched by the addition of a saturated aqueous ammonium chloride solution (10 mL) and water (10 mL). The mixture was extracted with ethyl acetate (2×40 mL), dried (MgSO4) and concentrated under reduced pressure to obtain the crude product. The crude residue was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to afford the title compound (1.8 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: COCCCN
Solvent: O
Solvent: CS(C)=O
Product: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (5.12 g, 21.6 mmol) in DMSO (20.5 mL) was added 3-methoxypropylamine (4.40 mL, 43.1 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to give a light yellow brown solid as 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, br. s.), 8.54 (1H, d, J=2.3 Hz), 8.43 (1H, d, J=2.3 Hz), 3.69-3.78 (2H, m), 3.56 (2H, t, J=5.7 Hz), 3.40 (3H, s), 1.96 (2H, dt, J=12.2, 6.2 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1[N:12]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:13]=[N:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 31.1 %

Procedure:
4-Fluoronitrobenzene (2 g, 0.014 mol), tetrazole (1 g, 0.014 mol), potassium carbonate (1.96 g, 0.014 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), the resulting yellow solid filtered of and dried in vacuo to afford the title compound (831 mg, 31%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][CH:3]=1.[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[CH2:21][O:22]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(CCCCc2ccccc2O)cc1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Example 1(a), 0.70 g of 2-[4-(4-methylphenyl)butyl]phenol (prepared as described in Preparation 6), 0.33 g of potassium t-butoxide and 0.8 g of epibromohydrin were reacted in 40 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 0.63 g (yield 73%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH:6](O)[CH2:5][C:4]1=[O:58])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C=CC1=O)C(C)CC2OC
Yield: 87.6 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount of p-toluenesulfonic acid in 40 ml of benzene was refluxed for 4 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the dark residue was purified by chromatography (silica gel, 7% i-propanol/CH2Cl2) to give 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (180 mg) as a white solid. This material was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was introduced via balloon for 30 min. and the mixture was filtered through celite. Removal of solvent followed by chromatography (silica gel) gave 172 mg of the title compound. Mass, 1H and 13C NMR data were consistant with the title structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(#N)C.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]2[S:38][C:37]3[N:39]4[C:30](=[CH:31][N:32]=[C:33]4[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)=[O:27])[CH2:21][CH2:20]1.[I-].[Na+]>C(N(CC)CC)C>[C:9]([C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26]([C:28]3[S:38][C:37]4[N:39]5[C:30](=[CH:31][N:32]=[C:33]5[CH:34]=[CH:35][CH:36]=4)[CH:29]=3)=[O:27])[CH2:23][CH2:24]2)[CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: N#Cc1cccc(OCCCCl)c1
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)c1
Yield: 57.4 %

Procedure:
3-(3-Chloropropan-1-yl)oxybenzonitrile (503 mg) was added, at room temperature, to an acetonitrile solution (20 ml) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8b-diazabicyclo[5.4.0]-7-undecene (662 mg), triethylamine (1.09 g) and sodium iodide (285 mg). The mixture was heated under reflux for 6.5 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with chloroform. The extract solution was washed with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (ethyl acetate/methanol=2/1) to afford the object compound (565 mg, 57%) as reddish purple crystals.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=S)[NH:7][NH2:8])([CH3:4])[CH3:3].Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S]>Cl>[CH3:1][C:2]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[NH:8][N:7]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [S]
Product: CCOC(=O)c1c(NC(C)(C)C)n[nH]c1C
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A solution of 25 g (0.17 mole) of 4-(1,1-dimethylethyl)-3-thiosemicarbazide in 85 mL of 2N ethanolic hydrogen chloride was cooled to 0° C. with an ice bath and while stirring under nitrogen atmosphere, 28 g (0.17 mole) of ethyl 2-chloroacetoacetate was added dropwise. The reaction mixture was allowed to come to room temperature while stirring for 16 hr. The pale yellow solution was then refluxed for 2 hr during which a film of sulfur deposited on the sides of the flask. The reaction mixture was cooled to room temperature and the sulfur removed by filtration. The filtrate was concentrated in vacuo to give 39 g of pale yellow oil which was dissolved in ligroin and, after standing at ~7-10° C. for ~60 hr, yielded 20.5 g of large crystals, mp 118°-119° C. An additional 6.1 g of crude material was obtained by reworking the residues.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:18][C:17]=2[N:16]([CH3:42])[C:14]1=[O:15])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]=1[CH2:12][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:18][C:17]=2[N:16]([CH3:42])[C:14]1=[O:15])#[N:2]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1OCC#N)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1c(C#N)oc3ccccc13)c(=O)n2C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 215 mg of 1-{2-[2-cyanomethoxy-phenyl]-2-oxo-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 244 mg of caesium carbonate in 4 ml of N,N-dimethylformamide is stirred for two hours at 50° C., then a further three hours at 70° C. For working up the reaction mixture is combined with water and the precipitate formed is suction filtered and dried.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34]O>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: NC(CO)Cc1ccccc1
Solvent: CCO
Product: NC(COB(c1ccccc1)C(OC(B(OCC(N)Cc1ccccc1)c1ccccc1)c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
The entitled compound (6 mg) was obtained by allowing 34 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 26 mg of 2-amino-3-phenylpropanol to act in 1 mLof ethanol.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[F:21][C:12]1[CH:11]=[CH:10][C:9]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:20][C:13]=1[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)NCc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(CNS(C)(=O)=O)c1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
Dissolve zinc (II) bromide (313 mg, 1.20 mmol) in tetrahydrofuran (2.5 mL) and treat with triethylamine (0.64 mL, 4.80 mmol). After 4 min add N-(5-bromo-2-fluorobenzyl)methanesulfonamide (282 mg, 1.00 mmol), (prepared as described in PREPARATION 35), trimethylsilylacetylene (0.30 mL, 2.12 mmol), and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.050 mmol) to the reddish solution. Heat to 60° C. in a sealed tube overnight, cool to room temperature and filter through diatomaceous earth with ethyl acetate. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with 75:25 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (220 mg, 74%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH3:22]O>>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: CN1CCN(c2ccc(CC(=O)O)cc2)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(N2CCN(C)CC2)cc1

Procedure:
Thionyl chloride (0.32 g, 2.77 mmol) was added dropwise to a suspension of 2-(4-(4-methylpiperazin-1-yl)phenyl)acetic acid (2.60 g, 11.1 mmol) in MeOH (30 ml) at 0° C. and refluxed for 5 h. The reaction mixture was concentrated and the residue was dissolved in water, made alkaline with saturated sodium bicarbonate solution up to pH˜8 and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to get the crude compound. The crude was purified by column chromatography over neutral alumina using 4% MeOH in DCM as eluent to afford 250 mg of methyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate as brown color solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH2:40][CH:35]([CH2:34][OH:33])[CH2:36]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: OCC1CCCNC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCC(CO)C3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 3-hydroxymethyl piperidine. A yellow solid 115 was obtained (0.0279 g, 60%). 1H-NMR (CDCl3, 400 MHz) δ 1.32-1.42 (m, 1H), 1.63-1.74 (m, 1H), 1.86-1.95 (m, 2H), 2.04-2.14 (m, 1H), 3.18-3.25 (m, 1H), 3.33-3.39 (m, 1H), 3.47-3.52 (m, 1H), 3.71 (dd, J=4.0 Hz, 11.0 Hz, 1H), 3.83 (s, 3H), 4.02-4.07 (m, 1H), 4.48-4.53 (m, 1H), 6.93 (d, J=6.6 Hz, 1H), 7.00-7.08 (m, 4H), 7.45-7.52 (m, 3H), 7.84 (s, 1H), 8.35 (d, J=6.5 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([OH:15])=O)[NH:9][C:10]=1[CH2:11][CH3:12]>>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([Cl:3])=[O:15])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Cl)nc1Cl
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
Thionyl chloride (4 mL) was added to 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1c, 200 mg, 0.8 mmol), and the mixture was stirred at 85° C. for 40 minutes. Following concentration under reduced pressure, the residue was azeotropically distilled with toluene twice to obtain crude 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid chloride. 5 mL pyridine was added and then ethyl 2-(4-aminophenyl)-1,3-thiazole-5-carboxylate obtained in Example (91b) was added. The mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate. The precipitated solid was collected by filtration and washed with ethyl acetate, to obtain 214 mg of the title compound as a white solid (73%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CO[C:14](OC)(N(C)C)[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:14]([CH3:15])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: COC(C)(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(Br)cc2)o1
Temperature: 60 °C

Procedure:
4-Bromo-benzoic acid hydrazide (12.90 g, 60 mmol) and N,N-dimethylacetamide dimethyl acetal (12 mL, 82.0 mmol) were dissolved in N,N-dimethylformamide (100 mL) and the solution heated to 60° C. for 2 hours. The solution was concentrated in vacuo and the residue taken up in toluene (80 mL) and treated with para-toluenesulfonic acid monohydrate (200 mg, 1.50 mmol). The mixture was heated to reflux for 2 hours, allowed to cool, and the product crystallised from the solution and was collected by filtration. The crude product was washed with ether and dried in vacuo to yield a white solid. The filtrate was concentrated in vacuo and the residue combined with the white solid, dissolved in toluene (50 mL) and treated with para-toluenesulfonic acid monohydrate (100 mg, 0.75 mmol). The mixture was heated to reflux for 3 hours, allowed to cool and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 80:20 to 40:60 to yield the title product, 12.00 g.