Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:47])[C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([NH:30][CH2:29][CH2:28][C:25]4[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=4)=[O:47])=[CH:33][CH:34]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CC1(C)OB(c2ccc(C(=O)NCCc3ccncc3)cc2)OC1(C)C
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
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: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4ccncc4)cc3)nc3scnc23)cc1OC
Yield: 31.5 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol) and N-(2-(pyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (140 mg, 0.4 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (64 mg, 0.6 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 16 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with EtOAc) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (50 mg, 31%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 10.15 (s, 1H), 9.37 (s, 1H), 8.68 (t, 1H, J=5.3 Hz), 8.46-8.42 (m, 4H), 7.94-7.91 (m, 2H), 7.81 (d, 1H, J=2.7 Hz), 7.52-7.47 (m, 1H), 7.27-7.26 (m, 2H), 7.00 (d, 1H, J=8.7 Hz), 4.02 (s, 3H), 4.00 (s, 3H), 3.58-3.52 (m, 2H), 2.89 (t, 2H, J=7.0 Hz). LC-MS: 513 [M+H]+, 511 [M−H]−, tR=1.32 min. HPLC: 97.72% at 214 nm, 96.31% at 254 nm, tR=4.19 min.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:13].[Br-].[Li+].C(N(C(C)C)CC)(C)C>O1CCCC1.O>[C:12]([C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:21][CH:20]=1)#[N:13]
Reactant: N#Cc1ccsc1-c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)C(Cc1ccc(-c2sccc2C#N)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 99.5 %

Procedure:
11 g of ethyl 3-oxohexanoate are dissolved in 150 ml of tetrahydrofuran. 12.9 g of 4-(3-cyano-2-thienyl)benzyl bromide and 6.1 g of lithium bromide are added and the mixture is stirred at room temperature. 24.2 ml of diisopropylethylamine are then added dropwise. After the addition is complete, the reaction mixture is brought to reflux for 24 hours. After evaporation under vacuum, the residue obtained is taken up with water and then extracted with chloroform. The organic phase is dried and then evaporated under vacuum. The excess ethyl 3-oxohexanoate is removed using a vane pump. 16.4 g of ethyl 2-[4-(3-cyano-2-thienyl)benzyl]-3-oxohexanoate are thereby obtained in the form of a pale yellow oil, which is used without further purification for the next step.
Reaction SMILES: Cl.[CH3:2]N(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][C@H:21]1[C:36]([OH:38])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH:39][N:40]1[C:44]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH:21]1[C:36](=[O:38])[N:40]([O:39][CH3:2])[CH3:44])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.11 g) was added over 5 minutes to a mixture of N,0-dimethylhydroxylamine hydrochloride (1.17 g), (2S)-piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.64 g), 1-hydroxybenzotriazole (1.49 g) and N,N-diisopropylethylamine (2.1 ml) in dichloromethane (40 ml). After being stirred for 18 hours at room temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:1) to give 2-(N-methoxy-N-methylcarbamoyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.61 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1ccccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 150 °C
Yield: 54.1 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(2-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.627 mmol), and hydrazine anhydrous (0.026 mL, 0.836 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (50 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.73 (m, 1H), 1.91-2.15 (m, 2H), 2.26 (m, 4H), 2.70-2.92 (m, 1H), 3.44 (m, 1H), 3.50-3.84 (m, 1H), 4.30 (d, J=12.6 Hz, 1H), 4.67-5.11 (m, 1H), 6.79-6.95 (m, 1H), 7.09-7.33 (m, 4H), 7.47 (d, J=7.8 Hz, 1H), 7.83 (s, 1H) 7.99 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([C:60](Cl)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:57]2[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=2)=[O:61])[CH2:48]1
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(C(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)n1
Yield: 82 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-3-carbonyl chloride as the starting materials in 82% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z=558.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([OH:13])[CH3:12].[OH-].[Na+].O>CN1CCCC1=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:13][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc([N+](=O)[O-])cc1

Procedure:
(a.) bringing p-nitrochlorobenzene, ethanol and 40-40-60% aqueous solution of sodium hydroxide into reactive contact at an elevated temperature in a cosolvent liquid system comprising the solvents of ethanol, water and N-methylpyrrolidone to ethoxylate the p-nitrochlorobenzene to produce p-nitrophenetole, the mol ratio of ethanol to p-nitrochlorobenzene being about 5:1 to 1:1 and the mol ratio of N-methylpyrrolidone to p-nitrochlorobenzene being about 4:1 to 1:1,
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].Cl.Cl.[CH2:10]([NH:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:10]([N:17]1[C:4]([CH3:5])=[CH:3][C:2]([CH3:1])=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(C)n(Cc2ccccc2)n1
Yield: 92 %

Procedure:
Dissolve 2,4-pentanedione (5.09 g, 50.8 mmol) and benzylhydrazine dihydrochloride (10.91 g, 55.9 mmol) in acetic acid (40 mL). Slowly add triethylamine (15.6 mL, 0.112 mol) and stir the mixture for 18 hr. Concentrate the solution then dilute the residue with saturated aqueous sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 40:60 hexanes:ethyl acetate), to give 1-benzyl-3,5-dimethyl-1H-pyrazole as a yellow oil (8.703 g, 92%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[S:59]1[CH:63]=[CH:62][CH:61]=[C:60]1[CH2:64][CH2:65][NH2:66]>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26](=[O:27])[NH:66][CH2:65][CH2:64][C:60]2[S:59][CH:63]=[CH:62][CH:61]=2)=[CH:18]1
Reactant: NCCc1cccs1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1cccs1
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.401 g, 1.01 mmol) in dry ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.02 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.199 g, 1.04 mmol). This mixture was stirred 2 hours, then triethylamine (0.18 mL, 1.3 mmol) and 2-thiopheneethaneamine hydrochloride (0.214 g, 1.30 mmol) were added. After stirring the resulting mixture an additional 18 hours, the mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, saturated aqueous sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, purified by flash chromatography (SiO4, 4×20 cm, 230-400 mesh, 67% ethyl acetate/hexane eluant), and dried for 48 hours under vacuum at 60° C. to provide 0.310 g (61%) of product; 1H NMR (CDCl3) δ 1.49-1.60 (2H, m), 1.55 (3H, s), 1.65-2.00 (12H, m), 2.88 (2H, t, J 6 Hz), 3.26 (1H, d, J 14 Hz), 3.40-3.60 (3H, m), 4.82 (1H, br s), 5.17 (1H, br s), 6.36 (1H, br s), 6.69 (1H, d, J 2 Hz), 6.85-6.90 (1H, m), 6.95 (1H, d, J 2 Hz), 7.00-7.22 (3H, m), 7.36 (1H, d, J 8 Hz), 7.58 (1H, d, J 8 Hz), 8.29 (1H, br s).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26]1(=[O:28])=[O:27]>CN(C)C=O>[O:27]=[S:26]1(=[O:28])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35](=[O:36])[N:25]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: NCC1CCc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCNCC1CCc2ccccc2O1
Temperature: 60 °C

Procedure:
The mixture of 5.4 g (0.033 (-)-2-aminomethylchroman example 92f; αD =-22.8), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-(4-bromobutyl)saccharin and 80 ml anhydrous dimethyl formamide was heated to 60° C. for 4 h. The solvent was evaporated at 0.01 torr. The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) and chromatographed on silica (300 g). The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica, providing 3.7 g of chemically pure 2-{N-[4-(1,1-Dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}chroman.
Reaction SMILES: [N+:1]([CH2:4][C:5](=[O:7])[CH3:6])([O-:3])=[O:2].C(O[CH:11]=[C:12]([C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C([O-])(=O)C.[Na+]>C(O)C>[OH:7][C:5]1[CH:6]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c([N+](=O)[O-])cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of nitro-2-propanone (63.50 g, 0.616 mol), (ethoxymethylene)oxalacetic acid, diethyl ester (151.1 g, 0.616 mol) and ethanol at 5° C. under a nitrogen atmosphere is treated with sodium acetate (101.1 g, 1.23 mol), stirred overnight at room temperature, and concentrated in vacuo. The resultant residue is chromatographed (silica gel, 1% ethyl acetate:hexanes eluent). The chromatographed material is taken up in ethyl acetate and extracted with an equivalent of aqueous sodium hydroxide. The basic layer is acidified to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract is dried and concentrated in vacuo to give the title product as a yellow oil, 16.0 g, identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:10]=1)[OH:11]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1O

Procedure:
A solution of 20.0 g of 5-aminosalicylic acid, 250 ml of methanol and 10 ml of concentrated sulfuric acid is refluxed overnight. The reaction mixture is cooled, made alkaline with dilute aqueous sodium carbonate solution and concentrated. The resulting solid is separated and washed with water. The solid is then washed with ether, and the ether is evaporated to dryness yielding a brown solid. The aqueous filtrate above is extracted with ether, the extract is dried over anhydrous sodium sulfate, and evaporated yielding a brown solid. The solids are combined and recrystallized from ether to afford 10.7 g of 5-aminosalicylic acid methyl ester.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:52]([C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:42](=[O:44])[CH3:43])=[CH:51][CH:50]=2)(=[O:54])=[O:53])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)cc1
Yield: 18.7 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.016 ml, 0.09 mmol) and 4-acetamidobenzenesulfonyl chloride (0.011 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (EtOAc) gave 0.006 g of a white solid. MS (ES): 643 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:17](I)[CH3:18]>>[CH2:17]([O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:13]1)[CH3:18]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Agent: [H-]
Agent: [Na+]
Product: CCOC1CN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 55.5 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol) was treated with 60% NaH in oil (60 mg, 1.5 mmol) and ethyl iodide (400 uL, 5 mmol) as above to yield 62 mg of product following purification by flash chromatography. ES-MS calcd for C10H13N3O3 (m/e) 223.23, obsd 224.1 (M+H).
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN[C@@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN[C@@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3R)-3-methylaminopyrrolidine (95 μl, 0.88 mmol) was added at 150° C. to a dimethyl sulfoxide (17 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (271 mg, 0.838 mmol) and triethylamine (156 μl, 1.09 mmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[F-:25].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>O1CCCC1.C(Cl)Cl>[F:25][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CF)c3c2)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00240 mol), 14.4 mL of a 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (0.0144 mol) and anhydrous p-toluenesulfonic acid (1.36 g, 0.00790 mol) in tetrahydrofuran is stirred at room temperature for 30 minutes, refluxed for three hours, stirred at room temperature for three days, refluxed for 22 hours, partially concentrated in vacuo, and diluted with ethyl acetate. The resultant mixture is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an orange solid. Column chromatography of the solid using silica gel and a 2.5% diethyl ether in methylene chloride solution gives the title product as a white solid (0.42 g, mp 201-202° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14].[NH2:20][C:21]1[N:26]=[C:25]([Cl:27])[CH:24]=[C:23]([CH3:28])[N:22]=1>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[C:23]([CH3:28])[N:22]=[C:21]([NH:20][C:17](=[O:18])[NH:16][S:13]([O:12][C:5]2[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:19])(=[O:15])=[O:14])[N:26]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: COC(=O)c1cccc(OC)c1OS(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(OC)c1OS(=O)(=O)NC(=O)Nc1nc(C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5.4 g (0.02 mol) of the product from Example 1 in 10 ml of methylene chloride is added dropwise to 2.9 g (0.02 mol) of 2-amino-4-chloro-6-methylpyrimidine in 50 ml of methylene chloride at 0° C. The mixture is subsequently stirred at 25° C. for 24 hours and diluted with 50 ml of methylene chloride, and the organic phase is washed twice with 50 ml of 2N hydrochloric acid each time and once with water. After drying with sodium sulfate and removing the solvent on a rotary evaporator, an oily product remains, which crystallizes on trituration with diisopropylether. 7.8 g (91% of theory of methyl 2-[3-(4-chloro-6-methylpyrimidin-2-yl)-ureidosulfonyloxy]-3-methoxybenzoate of melting point 140°-143° C. are obtained.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]=[C:7]=[CH:8][CH3:9]>>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:4]=[CH:3][C:2]1[CH:1]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=C=CC
Reactant: [Li]CCCC
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
75/25 Butadiene/styrene random copolymer was polymerized continuously using multichelic initiator in a reactor train consisting of two 3/8" diameter by 11" long Kenics static mixers as the scavenging reactor means, followed by a 5 gallon capacity stirred polymerization reactor. Fast poisons in the monomer, diluent, randomizer, and gel inhibitor were inactivated by adding to the feedstream in the scavenging reactors 0.02 phm n-butyllithium. This scavenging treatment allowed an increase in the 1,2-butadiene gel inhibitor level from 0.05 phm, which is typically used in this polymerization, to 0.08 phm while maintaining the desired 90-100 Mooney viscosity (ML-4 as described in ASTM D1646-74). This increase in gel inhibitor resulted in a 575-hour gel-free polymerization.