Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(O)(O)O>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: OP(O)O
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Temperature: 173 °C
Yield: 94 %

Procedure:
288 parts of β-naphthol, 220 parts of aniline and 5 parts of phosphorous acid are mixed and heated to 173° C. At this temperature, the elimination of water commences. The reaction temperature rises to 230° C in the course of 4 hours. At that stage, the reaction has ended and 36 parts of water have been removed. The further working up is carried out as described in Example 8. 412 parts of N-phenyl-β-naphthylamine of melting point 100° - 102° C are obtained, corresponding to a yield of 94% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:3]=1.CCO.O.[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:3]=1
Reactant: COC(=O)COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)cc(OCC(=O)O)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Methyl 2-(6-amino-3-((1-benzyl-1H-pyrazole-4-carboxamido)methyl)-2-methylpyridin-4-yloxy)acetate (28 mg, 0.051 mmol) was dissolved in THF, EtOH, H2O 2:1:1 (5 ml), then LiOH (4.31 mg, 0.103 mmol) was added and the reaction mixture was stirred at rt over night. After adjusting the pH to 4, the reaction mixture was evaporated, co-evaporated with Toluene (4 times) then dried under HV to get the title compound which was used for the next step without further purification. HPLC/MS (Method B) Rtb=0.43 min, MS [M+H]+=396.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[C:37]([CH2:39][C:40](O)=O)#[N:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:21]2[NH:20][C:19](=[O:31])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:8]4[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]5[CH:32]=[C:33]([CH3:36])[C:34]6[N:35]=[C:40]([CH2:39][C:37]#[N:38])[NH:1][C:2]=6[CH:3]=5)[CH:7]=4)[CH2:17][CH2:16]3)[CH2:24][CH2:23][C:22]=2[CH:25]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC#N)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 40 mg (0.46 mmol) cyanoacetic acid, 0.15 g (0.47 mmol) TBTU and 0.14 mL (1.00 mmol) TEA in 2.00 mL DMF were stirred for 4 h at RT. Then 2.00 mL glacial acetic acid was added and the mixture was stirred overnight at RT. The reaction mixture was also stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:21]=[N+:22]=[N-:23])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc2c(s1)C(N=[N+]=[N-])COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 110.5 %

Procedure:
To a stirred mixture of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in MeOH (20 mL) was added a solution of NaN3 (93.1 mg, 1.43 mmol) in water (2 mL) dropwise at room temperature. The mixture was heated to 60° C. overnight. The mixture was cooled to room temperature, and then 20 mL of water was added. The mixture was stirred for 0.5 h and then filtered to afford 4-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J=2.5 Hz, 1H), 7.56 (dd, J=8.7 Hz, J2=2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 5.35 (m, 1H), 4.75 (m, 1H), 4.33 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(#N)C.[N+:8]([C:11]1[CH:12]=[C:13]([N:20]=[C:21]=[O:22])[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)([O-:10])=[O:9]>O>[N+:8]([C:11]1[CH:12]=[C:13]([NH:20][C:21]([NH:1][CH2:2][CH2:3][OH:4])=[O:22])[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)([O-:10])=[O:9]
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CC#N
Solvent: O
Product: O=C(NCCO)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
11.0 g (0.180 mol) of 2-aminoethanol was placed, in a nitrogen current, in a 0.3-l four-necked flask equipped with a nitrogen inlet tube, a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added 50 ml of acetonitrile, followed by stirring for dissolution. While the flask was being cooled with ice water, the flask contents were stirred. Thereto was dropwise added 50 ml of the above-obtained acetonitrile solution containing 3,5-dinitrophenyl isocyanate (compound 7). The mixture was stirred at room temperature for 1 hour and then poured into 0.7 l of water. The separated crystals were collected by suction filtration, washed with water and vacuum-dried at 35° C. for 12 hours to obtain N-(3,5-dinitrophenyl)-N'-(2-hydroxyethyl)urea (compound 11) as a yellow powder. Yield: 16.7 g (74%) Melting point: 192-194° C.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>N1C=CC=CC=1>[CH3:2][S:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ccc2c(c1)C(CCN)CCC2
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccc2c(c1)C(CCNC(C)=O)CCC2
Reaction time: 5 h

Procedure:
In a 50 ml round-bottomed flask, 0.0025 mol of the compound obtained in Step E is dissolved in 5 ml of pyridine. The solution is cooled with the aid of an ice bath and 5 ml of acetic anhydride are added dropwise. Stirring is carried out for 5 hours at ambient temperature. The reaction mixture is poured into aqueous 3M hydrochloric acid solution and is then extracted with ethyl ether. The organic phase is washed with aqueous 10% potassium carbonate solution and then with water, is dried over magnesium sulphate and is evaporated under reduced pressure. The residue obtained is recrystallised.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:17]2[N:35](CC(=O)C3C=CC=CC=3)[CH2:36][NH:37][C:16]=2[CH2:15]1)=[O:13].C(#N)C>CCOCC>[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C:17]2[N:35]=[CH:36][N:37]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=3)[C:16]=2[CH2:15]1)=[O:13]
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Reactant: Cc1cccc(CBr)c1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1Cc2c(ncn2Cc2cccc(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2.7 mL 3-methylbenzyl bromide, 5.0 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 50 mL acetonitrile is heated at reflux 4 hr. The cooled solution is added dropwise to 750 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 75 mL methanol and treated with 16 g zinc dust and 75 mL acetic acid. The resulting suspension is sonicated 6 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 650 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99.5:0.5) as a crisp foam. NMR (CDCl3) 4.97 (s, 2H, NCH2Ar).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:29][C:30]2(O)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:6]2[C:7]([O:27][CH3:28])=[N:8][N:9]3[C:13]([C:14]4[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][O:23][CH3:24])=[CH:16][C:15]=4[O:25][CH3:26])=[CH:12][S:11][C:10]=23)[CH2:3][CH2:2]1.C(N(S(F)(F)[F:43])CC)C.C(=O)([O-])O>ClCCl>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([O:27][CH3:28])=[N:8][N:9]3[C:13]([C:14]4[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][O:23][CH3:24])=[CH:16][C:15]=4[O:25][CH3:26])=[CH:12][S:11][C:10]=23)[CH2:29][C:30]2([F:43])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:3][CH2:2]1.[CH:1]1([CH2:4][N:5]([CH2:29][C:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]=2)[C:6]2[C:7]([O:27][CH3:28])=[N:8][N:9]3[C:13]([C:14]4[C:15]([O:25][CH3:26])=[CH:16][C:17]([CH2:22][O:23][CH3:24])=[CH:18][C:19]=4[O:20][CH3:21])=[CH:12][S:11][C:10]=23)[CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCc1cc(OC)c(-c2csc3c(N(CC4CC4)CC4(O)CCOCC4)c(OC)nn23)c(OC)c1
Agent: O=C([O-])O
Solvent: ClCCl
Product: COCc1cc(OC)c(-c2csc3c(N(CC4=CCOCC4)CC4CC4)c(OC)nn23)c(OC)c1
Product: COCc1cc(OC)c(-c2csc3c(N(CC4CC4)CC4(F)CCOCC4)c(OC)nn23)c(OC)c1
Reaction time: 0.08 h

Procedure:
To a dichloromethane (4 mL) solution of 4-({cyclopropylmethyl-[3-(2,6-dimethoxy-4-methoxymethyl-phenyl)-6-methoxy-pyrazolo[5,1-b][1,3]thiazol-7-yl]-amino}-methyl)-tetrahydro-pyran-4-ol (64.5 mg, 0.124 mmol) was added dropwise diethylaminosulfur trifluoride (DAST) (24.6 μL, 0.186 mmol), and the mixture was stirred for five minutes. After the reaction was completed, a saturated aqueous solution of hydrogencarbonate was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by HPLC to obtain cyclopropylmethyl-[3-(2,6-dimethoxy-4-methoxymethyl-phenyl)-6-methoxy-pyrazolo[5,1-b][1,3]thiazol-7-yl]-(4-fluoro-tetrahydro-pyran-4-ylmethyl)-amine (8.9 mg, 0.017 mmol) and cyclopropylmethyl-(3,6-dihydro-2H-pyran-4-ylmethyl)-[3-(2,6-dimethoxy-4-methoxymethyl-phenyl)-6-methoxy-pyrazolo[5,1-b][1,3]thiazol-7-yl]-amine (1.3 mg, 0.003 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:15].[Cl:15][CH2:14][CH2:13][CH2:12][N:7]1[CH2:8][CH2:9][O:10][C@H:5]([CH2:4][O:3][CH3:2])[CH2:6]1
Reactant: ClCCCBr
Reactant: COC[C@@H]1CNCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1CN(CCCCl)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2S)-2-(methoxymethyl)morpholine hydrochloride (0.5 g), 1-bromo-3-chloropropane (1.47 ml) and potassium carbonate (2.06 g) in N,N-dimethylformamide (6 ml) was stirred at room temperature for 1 hour. After ethyl acetate and water were added to the mixture, the organic layer was separated, washed with water twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting oil was treated with 4N hydrogen chloride in ethyl acetate to give (2S)-4-(3-chloropropyl)-2-(methoxymethyl)morpholine hydrochloride (0.44 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][C:19]1[C:36]([CH3:37])=[CH:35][C:22]2[NH:23][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][NH:31][CH2:30]4)=[N:25][C:21]=2[CH:20]=1.O>CN(C)C=O>[CH3:37][C:36]1[C:19]([CH3:18])=[CH:20][C:21]2[NH:25][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)[CH2:30]4)=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCNC4)[nH]c2cc1C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
287 mg of 2-chloro-5-nitropyridine and 500 mg of potassium carbonate are added to a solution of 500 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine hydrochloride in 5 ml of dimethylformamide. After stirring for 20 hours at ambient temperature, the reaction medium is added to 50 ml of water. The precipitate formed is recovered by filtration through sintered glass, washed with 3 times 15 ml of water and then dried under reduced pressure. 548 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-c]pyridine are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:14][CH2:15][OH:16])[CH2:12]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(Cl)Cl>[CH3:25][S:26]([O:16][CH2:15][CH2:14][CH:11]1[CH2:12][N@@:10]1[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=1)(=[O:9])=[O:8])(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)N[C@H](CO)CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2CCOS(C)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)[N@]2CC2CCOS(C)(=O)=O)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
(S)-2-(p-Toluenesulfonylamino)-1,4-butanediol, 2, (46 g) was dissolved in methylene chloride (450 mL) and triethylamine (60 g) was added. The resulting solution was cooled to -5° C. under a nitrogen atmosphere and a solution of methanesulfonyl chloride (42.0 g) in methylene chloride (110 mL) was added dropwise over 3 hours. The resulting mixture was stirred an additional 0.5 hour at 0° to -5° C. and water (150 mL) and methylene chloride (350 mL) were cautiously added. The layers were separated and the organic layer extracted with 0.1N HCl (100 mL) and demineralized water (100 mL) and then concentrated under vacuum to give (S)-2-(2'-methanesulfonyloxyethyl)-1-(p-toluenesulfonyl)aziridine, 3, as a light yellow solid (57.2 g) which was used directly in the next step without further purification. A portion was recrystallized from ethyl acetate and hexanes: mp 78°-80° C.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.BrC1C=CC(C#N)=CC=1.[OH-:19].[Cs+]>>[OH:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(I)cc1
Agent: N#Cc1ccc(Br)cc1
Agent: [Cs+]
Product: N#Cc1ccc(O)cc1

Procedure:
Following general operating mode A, 4-iodobenzonitrile or 4-bromobenzonitrile (229 mg or 182 mg, 1.0 mmol) were reacted at respectively 110° C. or 130° C. with cesium hydroxide to afford the expected product in the form of a white solid at respective yields of 91% and 94% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: ClCl.CO.C.[CH3:6][CH2:7][CH2:8][CH2:9]CCCC[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N+]1C=CC=CC=1.[Cl-]>C(Cl)(Cl)(Cl)Cl>[CH2:6]=[CH:7][CH:8]=[CH2:9].[CH2:21]=[CH:20][C:19]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCCCCCCCCCC[n+]1ccccc1
Agent: C
Agent: ClCl
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: C=CC=C
Product: C=Cc1ccccc1
Reaction time: 1 h

Procedure:
In an evacuated one liter beverage bottle equipped with a rubber septum and stir bar was added ten grams of polymer XVIII in carbon tetrachloride (100 grams). The solution was treated with 900 milliliters (0.04 mol, 2.6 grams) of chlorine gas introduced into the solution via cannula. After one hour, methanol (500 milliliters) was added to the reaction mixture to precipitate a white product. After filtration and vacuum drying, the resultant polymer had two glass transition temperatures at 50° and 72° C. as determined by DSC. The area under the 72° C. glass transition was approximately one-third the area under the 52° C. transition. When the same reaction was repeated using 450 milliliters of (0.02 mol, 1.3 grams) chlorine gas under the same conditions, a polymer product was obtained with a glass transition temperature at 50° C. The minimum fix temperature of this polymer as toner by extrusion with 6 weight percent of Regal® 330 carbon black and 2 percent of cetyl pyridinium chloride charge control agent was 240° F. and the hot offset temperature was 290° F. with a Xerox Corporation 5028™ silicone roll fuser operated at 3.3 inches per second.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]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(N(CC)CC)C>C(Cl)Cl>[S:23]([C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
3-Hydroxy-Cbz-(R)-pyrrolidine (13.7 g, 0.06 mol) was dissolved in CH2Cl2 (250 mL) and cooled to 0° C. p-Toluenesulfonyl chloride (14.16 g, 0.07 mol), and triethylamine (20.7 mL, 0.15 mol) were added and the resulting solution was stirred for 4 h at 0° C. The solution was washed with 1 M HCl, saturated NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (3/1, v/v) to afford 20.4 g (88% yield) of the desired product as an oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl/[C:6](=[N:12]/[OH:13])/[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[OH:4][CH2:1][C:2]1[O:13][N:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=CCO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
24.03 g of 2-propene-1-ol and 16.24 g of ethyl (2E)-chloro(hydroxyimino)acetate were dissolved in 100 ml of tetrahydrofuran, and 12.12 ml of triethylamine dissolved in 50 ml of tetrahydrofuran was then added dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight. After aqueous saturated sodium chloride was added, the reaction mixture was separated into layers. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over aqueous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 14.22 g of ethyl 5-(hydroxymethyl)-isoxazole-3-carboxylate.
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[C@@H:13]([NH2:15])[CH3:14])=[CH:8][CH:7]=1)[CH3:3].CN(C)C(N(C)C)=N.[F:41][C:42]([F:49])([F:48])[C:43](OCC)=[O:44]>CO>[CH2:2]([S:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:21]=[CH:20]3)[C@@H:13]([NH:15][C:43](=[O:44])[C:42]([F:49])([F:48])[F:41])[CH3:14])=[CH:10][CH:11]=1)[CH3:3]
Reactant: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)cc1

Procedure:
(1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (50 mg, 0.11 mmol), 1,1,3,3-tetramethylguanidine (100 μl, 0.79 mmol) and ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5 mL) was stirred at r.t. for 1 h. The reaction mixture was concentrated by evaporation and the residual material was purified by HPLC. Yield 35 mg (62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:18]3[CH2:19][CH2:20][CH2:21][C:22](=O)[C:17]=3[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[OH2:26].Cl.[NH2:28]O.C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:18]3[CH2:19][CH2:20][CH2:21]/[C:22](=[N:28]/[OH:26])/[C:17]=3[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O
Reactant: NO
Reactant: CN(C[C@@H](O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(C[C@@H](O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Temperature: 50 °C

Procedure:
To a solution of N-[(2S)-2-(4-fluorophenyl)-2-hydroxyethyl]-N-methyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-sulfonamide (the compound of Preparation Example 49) (370 mg) in ethanol (4 mL) and water (2 mL) was added hydroxylamine.hydrochloride (100 mg) and sodium acetate (118 mg). After heating at 50° C. for 4 hours, the reaction solution was cooled to room temperature, the solution was dilued with water and extracted with ethyl acetate, and then was washed with saturated sodium chloride water. The crude product that was obtained after drying the solution with anhydrous sodium sulfate and removing the solvent by evaporation was purified by silica gel column chromatography (ethyl acetate/hexane; ethyl acetate 10–40%), fraction that was eluted with a solvent of higher polarity (the fractions that demonstrated low Rf values) was collected, and the title compound (280 mg) was obtained as a colorless solid. The NMR data of the present compound were consistent with those described in Example 1
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:26][CH:27]([F:29])[F:28])=[CH:15][CH:14]=2)=O)=CC=1)([O-])=O.[NH2:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[C:37]#[N:38]>>[C:37]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[NH:30][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:25][CH2:24][CH2:23]3)=[N:18][C:17]=2[C:16]([O:26][CH:27]([F:29])[F:28])=[CH:15][CH:14]=1)=[O:10])#[N:38]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2nc(N3CCC3)oc12
Reactant: Cn1ncc(C#N)c1N
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2nc(N3CCC3)oc12
Yield: 72.7 %

Procedure:
Starting from 2-(azetidin-1-yl)-4-difluoromethoxybenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (178 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (107 mg). Purification by column chromatography on silica eluting with 3% methanol in dichloromethane followed by trituration in diethyl ether afforded the title compound as a white solid (124 mg).