Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][O:21][CH3:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.[B:35](OC(C)C)([O:40]C(C)C)[O:36]C(C)C.[Li]CCCC>CCOC(C)=O>[CH3:22][O:21][CH2:20][O:19][C:14]1[CH:13]=[C:12]([O:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][C:15]=1[B:35]([OH:40])[OH:36]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution (0.30 M) of 4-bromo-3-(methoxymethoxy)phenyl 4-methylbenzenesulfonate in a mixture (1:3) of THF/toluene, triisopropyl borate was added and then the mixture cooled to −78° C. To the cold solution, n-BuLi (2.5 M in hexane; 1.5 eq) was added via syringe pump over 1.5 h. The mixture was stirred at −78° C. for a further 2 h and then left to warm to RT overnight. The mixture was diluted with EtOAc and washed with 1 N HCl, extracting the aqueous fraction a further two times with EtOAc. The combined organics were washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product, that could be used directly as crude or purified by FC (PE/EtOAc 9/1) to afford the title compound (43%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.42 (s, 3H), 3.31 (s, 3H), 5.06 (s, 2H), 6.64-6.69 (m, 2H), 7.44-7.49 (m, 3H), 7.74 (d, J 8.3, 2H); (ES+) m/z 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](I)[CH3:12].C(=O)([O-])O.[Na+].C(O)C>O>[CH3:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([NH:8][CH2:11][CH3:12])=[CH:6][C:5]=1[OH:9]
Reactant: CCI
Reactant: Cc1cc(Cl)c(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNc1cc(O)c(C)cc1Cl

Procedure:
A mixture of 3 g of 4-chloro-2-methyl-5-aminophenol (0.016 mol), 2.6 g of ethyliodide (0.017 mol), 1.35 g of sodium hydrogen carbonate (0.016 mol) and 30 ml of ethanol was refluxed for 7 hours. After cooling and dilution with 50 ml of water, the solution was neutralized with a sodium hydrogen carbonate solution and then extracted three times with 50 ml of ethylacetate. The extract was dried over sodium sulfate and concentrated to dryness. The residue was recrystallized from toluene. Beige crystals melting at 205° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6](=[O:26])[N:7]([C@@H:9]([CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:10][OH:11])[CH3:8].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[CH:36][C:37](C(O)=O)=[N:38][CH:39]=1.C[C:46]([N:48](C)C)=[O:47].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[F:44][C:33]([F:32])([F:43])[C:34]1[CH:35]=[CH:36][C:37]([NH:48][C:46](=[O:47])[O:11][CH2:10][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:2]=2[Cl:1])=[O:26])[CH2:12][CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[N:38][CH:39]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)N(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN1C(=O)c2ccccc2C1=O)COC(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Yield: 52.4 %

Procedure:
To a solution of (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea (200 mg, 0.45 mmol), 5-(trifluoromethyl)picolinic acid (256 mg, 1.35 mmol) and DMA (0.3 mL, 1.35 mmol) in toluene (5 mL) was added DPPA (0.27 mL, 1.35 mmol). The mixture was heated to 100° C. for 2 h, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(1,3-dioxoisoindolin-2-yl)pentyl 5-(trifluoromethyl)pyridin-2-ylcarbamate (150 mg, 80%). LRMS (M+Na+) m/z 658.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1)c1ccccc1

Procedure:
The title compound was prepared from 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163) and phenylsulfonyl chloride (Aldrich) analogous to the conditions described in Example 172. Mp: 168–170° C. MS (ESI, pos. ion) m/z: 523.1 (M+1).
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([O:12]C)[CH:8]=[CH:7][C:6]=1[C:14]([C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[CH:18][CH:17]=1)=[O:15].O.C(O)(=O)C>CS(C)=O>[Cl:11][C:10]1[C:5]([Cl:4])=[C:6]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:19]=[CH:18][CH:17]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: COc1ccc(C(=O)c2ccnn2Cc2ccccc2)c(Cl)c1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C(c1ccc(O)c(Cl)c1Cl)c1ccnn1Cc1ccccc1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
0.95 g of sodium cyanide is added to a solution of 1.0 g of (2,3-dichloro-4-methoxyphenyl)(1-benzyl-5-pyrazolyl)methanone in dimethylsulfoxide and the mixture is heated at 100° C. for 4 hours under argon gas atmosphere. After cooling, cold water is added to the reaction mixture. The mixture is adjusted to pH 5-6 with acetic acid and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 0.39 g of 2,3-dichloro-4-(1-benzyl-5-pyrazolylcarbonyl)phenol.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1([CH3:26])[CH2:21][N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-])=[CH:11][C:10]=3[N:20]=[C:7]2[CH2:6][N:5]1[S:22]([CH3:25])(=[O:24])=[O:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH3:3][C:4]1([CH3:26])[CH2:21][N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([NH2:2])[C:10]=3[N:20]=[C:7]2[CH2:6][N:5]1[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CC1(C)Cn2c(nc3c[n+]([O-])c4ccccc4c32)CN1S(C)(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)Cn2c(nc3c(N)nc4ccccc4c32)CN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ammonium hydroxide (5 mL) was added with vigorous stirring to a suspension of 10,10-dimethyl-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline (0.91 g, 2.6 mmol) in dichloromethane (25 mL). p-Toluenesulfonyl chloride (0.50 g, 2.6 mmol) was added in one portion, and the reaction was stirred for four hours at ambient temperature. The organic layer was separated and washed with 1% aqueous sodium carbonate (50 mL) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid (0.77 g) was recrystallized from 1,2-dichloroethane to provide 10,10-dimethyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 227-228° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[O:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:27](=[O:30])([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:12]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:1][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([O:30][C:27]4[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=4)=[CH:26][CH:25]=3)=[N:3]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c[nH]nc1O
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (8.95 g), 4-phenoxybenzyl chloride (25.35 g), potassium carbonate (31.88 g), and N,N-dimethylformamide (200 ml) was stirred at 90° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyloxy)-1H-pyrazole-4-carboxylate (22.71 g, yield: 76%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[C:20](Cl)([Cl:22])=[O:21].C1(C)C=CC=CC=1>O1CCCC1>[Cl:22][C:20]([N:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])=[O:21]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 0.961 g (5.62 mmol) of t-butyl prolinate and 0.80 ml (5.76 mmol) of triethylamine in 4.2 ml of dry tetrahydrofuran was added dropwise to a stirring solution of phosgene in toluene (12.5%, 5.9 ml, 6.74 mmol) precooled to 0°. The reaction was allowed to warm to room temperature and stirred for an additional hour. After filtering and concentrating, a yellow oil was obtained which was used directly for the next step, B.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[N:25]=[C:26]=[O:27])[CH2:22]2>>[CH:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][CH:15]([CH2:22]3)[CH:16]1[NH:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][O:7]3)[CH2:3][CH2:2]1)=[O:27])[CH2:18]2
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)OCc1ccccc12

Procedure:
The title compound was prepared from 3H-spiro[isobenzofuran-1,4′-piperidine] following a procedure analogous to that described in Example 79 Step 2 using 2-adamantyl isocyanate in place of 2-adamantyl chloroformate. LC-MS Method 1 tR=2.03 min, m/z=367; 1H NMR (CDCl3) δ=1.60-2.00 (18H), 3.29 (m, 2H), 3.94 (m, 2H), 3.99 (s, 1H), 4.95 (1H), 5.08 (s, 2H), 7.05-7.35 (4H).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3](O)=O.C(N(CC)CC)C.FC(F)(F)[C:17](OCC)=[O:18].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:49][CH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>>[CH:17]([NH:1][C:2]([C:3]1[N:55]2[C:51]([S:52][CH:53]=[CH:54]2)=[CH:50][N:49]=1)([CH3:7])[CH3:6])=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(N)C(=O)O
Reactant: NCc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(NC=O)c1ncc2sccn12
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To 2.5 g (0.024m mole) of 2-amino-2-methylpropanoic acid was added under ice-cooling 17 ml (0.122 mole) of triethylamine, followed by 15 ml (0.14 mole) of ethyl trifluoroacetate, and the mixture was stirred for 1 hour. Six milliliter (0.05 mole) of ethyl trifluoroacetate was added, and the mixture was further stirred for 20 hours. The reaction mixture was concentrated to dryness under reduced pressure. To the solution of the residue thus obtained in methylene chloride (20 ml) was added 5 g (0.036 mole) of 1-hydroxybenzotriazole at a temperature of 3° C., followed by 38 ml (0.036 mole) of 1.0M dicyclohexylcarbodiimide and 2.85 g (0.025 mole) of 2-aminomethylthiazole. The mixture was treated in the same manner as in Preparation 16 (a) to give 4.9 g of the title compound. Yield 66%. NMR (CDCl3) δ: 1.71 (6H, s), 4.80 (2H, d, J=5.6 Hz), 7.03 (1H, brs), 7.33 (1H, d, J=3.3 Hz), 7.72 (1H, d, J=3.3 Hz), 7.81 (1H, brs).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][OH:37])[N:20]=[C:19]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Br:44][C:45]1[CH:46]=[N:47][C:48](Cl)=[N:49][CH:50]=1>CN(C=O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][O:37][C:48]3[N:49]=[CH:50][C:45]([Br:44])=[CH:46][N:47]=3)[N:20]=[C:19]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:18]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCO
Reactant: Clc1ncc(Br)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCOc1ncc(Br)cn1
Yield: 94.5 %

Procedure:
To a suspension of 9 mg of NaH 55% dispersion in mineral oil in 4 ml of DMF:THF 1:1 was added 50 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide (Example 14). After the evolution of gas had ceased, 42 mg of 5-bromo-2-chloropyrimidine was added and the mixture was stirred for 1 h at 650C before it was diluted with 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated, washed with 50 ml of water, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 3:2 to give 60 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a colourless foam. MS: tR=6.14 min, [M+1]+=739.18, [M−1]+=741.32.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[O:15][CH:14]([CH3:16])[CH2:13][C:12]2=[C:17]([NH2:19])[CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:5])[NH:19][C:17]1[C:12]2[CH2:13][CH:14]([CH3:16])[O:15][C:11]=2[CH:10]=[C:9]([O:8][CH3:7])[CH:18]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cc(OC)cc2c1CC(C)O2
Reaction time: 3 h

Procedure:
55.75 grams of ethylchlorocarbonate in 100 cc of anhydrous benzene are gradually added at 5° C. to a stirred solution of 81 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 46 cc of triethylamine in 700 cc of anhydrous benzene. At the end of the addition, the reaction mixture is slightly warmed and stirring is continued, at room temperature, for 3 hours. After this time the reaction mixture is refluxed for two hours, then cooled, washed with water, dried over Na2SO4 and concentrated to dryness yielding 95.81 grams (83.5 percent of theoretical) of the compound of the title B.p./0.4 mmHg 172° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][N:5]1[C:17](=[O:28])[CH:18]([NH2:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:2]=[CH2:3].[C:29]([N:36]1[CH:45]([C:46](O)=[O:47])[CH2:44][CH:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH2:42]2)[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:31][C:29]([N:36]1[CH:45]([C:46](=[O:47])[NH:27][CH:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]([N:5]2[CH2:6][CH:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH:4]2[CH2:1][CH:2]=[CH2:3])=[O:28])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC2=CC=CCC2CC1C(=O)O
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(N)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To solution of 1-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-2-amino-3-(4-fluorophenyl)-propan-1-one, 54, (1.4 mmol) is dissolved in DMF (10 mL) are added N-Boc-tetrahydroisoquinoline-3-carboxylic acid (0.47 g, 1.5 mmol), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol), N-methylmorpholine (0.84 g, 8.3 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.32 g, 1.7 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then warmed to room temperature and stirred an additional 1.5 hour. The reaction is quenched with saturated NH4Cl solution and then extracted 3 times with EtOAc (70 mL). The organic layers are combined, washed with saturated NaCl solution, dried over Na2SO4, and the solvent is removed in vacuo. The crude product is purified over silica to afford 0.69 g (77% yield) of the desired product as a white solid. 1H NMR (300 MHz, MeOD, Rotamers) δ 6.90–7.41 (m, 13H), 5.55–5.81 (m, 1H), 4.32–5.12 (m, 8H), 3.94–4.18 (m, 2H), 2.75–3.89 (m, 6H), 2.39–2.64 (m, 1H), 1.78–2.29 (m, 2H), 1.20–1.64 (m, 10H); MS (ESMS) m/z 642.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:15][CH2:14][O:13][C:5]=2[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[C:5]2[O:13][CH2:14][O:15][C:4]=2[C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c2c(c1Br)OCO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 51 %

Procedure:
In 35 ml of acetic acid was dissolved 10.5 g of methyl 5-methoxy-3,4-methylenedioxybenzoate, and a solution of bromine (formed by diluting 8 g of bromine with 25 ml of acetic acid) was dropped into the solution over a period of 1 hour. The mixture was stirred at room temperature for 10 hours and the reaction liquid was poured into ice water, and the formed precipitate was recovered by filtration and recrystallized from ethanol to obtain methyl 2-bromo-5-methoxy-3,4-methylenedioxybenzoate (the yield was 51%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=O)[NH:8][C:9]=1[C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:3])[CH3:2].[C:22](=[O:25])([O-])[O-].[K+].[K+].[CH3:28]N(C=O)C>>[CH2:7]([N:8]1[C:9]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:22]1=[O:25])[CH3:28]
Reactant: CC(C)c1c(-c2cnc3ccccc3c2)[nH]c(=O)[nH]c1=O
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(-c2cnc3ccccc3c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
5-Isopropyl-6-quinolin-3-yl-1H-pyrimidine-2,4-dione (6 mg, 0.021 mmol, 1.0 eq.) was dissolved in 0.5 mL DMF. Potassium carbonate (3 mg, 1 eq.) was added and the reaction mixture was stirred at room temperature for 10 minutes. Ed (1.7 μL, 1 eq.) was added. The reaction mixture was stirred at room temperature overnight. No reaction was observed. More potassium carbonate (6 mg) was added. The reaction mixture was complete after 2 hours. The reaction crude was filtered and purified by reverse phase HPLC to give a white powder (1.5 mg, 23%). LC-MS shows 310.2 (M+1). 1H-NMR (300 MHz, CDCl3): δ 8.83 (s, 1H), 8.40 (m, 1H), 8.22 (m, 1H), 7.96 (m, 2H), 7.78 (m, 1H), 3.58 (m, 2H), 2.10 (m, 1H), 1.90 (dd, 6H), 1.04 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([N:17]2[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Product: CCCCCCCCCCCCCc1nc2cnccc2n1-c1ccccc1
Yield: 33.9 %

Procedure:
Method B applied to 4-chloro-3-nitropyridine (79 mg, 0.5 mmol) and tetradecanoic acid phenylamide (182 mg, 0.6 mmol) afforded the title compound as viscous oil (64 mg, 34%). 1H NMR (DMSO) δ 0.83 (t, J=6.7Hz, 3H), 1.16-1.32 (m, 20H), 1.73 (p, J=6.7 Hz, 2H), 2.83 (t, J=6.7Hz, 2H). 7.63-7.71 (m, 6H), 8.56 (d, J=5.2Hz, 1H), 9.43 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[O:10].[CH2:12](OC(OCC)OCC)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:12]=[N:11][C:9]([OH:10])=[N:8]1
Reactant: NC(=O)NNc1ccccn1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: Oc1ncn(-c2ccccn2)n1
Temperature: 15 °C

Procedure:
A mixture of 31.9 g (0.21 m) of 2-pyridinylhydrazinecarboxamide and 17.50 ml of triethylorthoformate was refluxed for 6 hours with the ethanol formed as a by-product being continuously removed by distillation thereby maintaining the reaction temperature at 130°-140° C. At the completion of the reaction, the reaction mixture was cooled to 15° C. and the solid 1-(2-pyridinyl)-1H-1,2,4-triazol-3-ol product was recovered by filtration. The product after washing with methylene chloride was recovered in a yield of 25.2 g (74 percent of theoretical). The product melted at 260°-262° C. and upon analysis was found to have carbon, hydrogen, and nitrogen contents of 52.26, 3.90 and 34.79 percent, respectively, as compared with the theoretical contents of 51.89, 3.73 and 34.55 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1>C(N(CC)CC)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(C#C[Si](C)(C)C)s1
Yield: 92.6 %

Procedure:
Under a dry nitrogen atmosphere 3.0 grams (0.031 mole) of trimethylsilylacetylene was added to a stirred mixture of 5.5 grams (0.025 mole) of 2-iodo-5-methylthiophene in 50 ml of triethylamine. To this mixture was added approximately 0.05 gram of dichlorobis(triphenylphosphine)palladium (II) and approximately 0.05 gram of copper (I) iodide. The resultant mixture was stirred at room temperature for approximately 18 hours. The triethylamine was removed from the mixture by evaporation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and the resultant solution was washed in succession with an aqueous, 10% ammonium chloride solution, water, and an aqueous, saturated sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with n-hexane, to yield 4.5 grams of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne as an oil.