Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13].[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>CC1C=CC=CC=1C.C(OCC)(=O)C>[CH2:21]([O:23][P:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])([O:25][CH2:26][CH3:27])=[O:28])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C)OCC
Temperature: 25 °C
Yield: 58 %

Procedure:
2-Bromomethyl-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester (Example 44, 2.0 g, 5.46 mmol) was dissolved in 100 mnL of anhydrous o-xylene. To this solution was added triethylphosphite (3.75 mL, 21.84 mmol). A water cooled condenser was attached and the material was heated to exactly 100° C. After six hours the mixture was cooled to room temperature then diluted with with ethyl acetate (400 mL) and washed with brine (2×). After drying over MgSO4 the organic layer was concentrated on a rotovap and then purified by flash column chromatography using 50 to 60% ethyl acetate/hexanes gradient as an eluant to provide 1.34 g of the title compound as a yellow oil.(55%): 1HNMR (CDCl3) δ8.87 (m, 1H), 8.43 (dd, J=9 Hz, 2 Hz, 1H), 8.05 (dd, J=9 Hz, 2 Hz, 1H), 4.12 (m, 4H), 3.81 (s, 2H), 3.77 (d, J=23 Hz, 2H), 1.32 (m, 6H), 0.96 (s, 9H); MS (ES-POS): [M+Na]+ 446; Analytical HPLC determined that this compound was 96.1% pure by C-18 reverse phase.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)cc(C)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)nc(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-4-(4-amino-3-methoxypiperidin-1-yl)-6-methylpyridine-2-carboxylate obtained in Example (168b) (129 mg, 0.44 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (64 mg, 0.37 mmol), WSC hydrochloride (211 mg, 1.1 mmol) and HOBt (49.7 mg, 0.37 mmol), to obtain 174 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])=[N:8][CH:7]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:3]([CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])=[N:8][CH:7]=1)([OH:21])=[O:2]
Reactant: COC(=O)CCc1cnc(-c2cccc(C(=O)OC)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CCc1cnc(-c2cccc(C(=O)O)c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 3-[5-(3-methoxy-3-oxopropyl)-1,3-oxazol-2-yl]benzoate (400 mg, 1.3 mmol) in 2:1:1 tetrahydrofuran/methanol/water (8 mL) is added lithium hydroxide monohydrate (112 mg, 2.7 mmol), and the reaction is stirred 2 h at room temperature. More lithium hydroxide monohydrate (225 mg, 5.4 mmol) is added and the reaction is stirred 16 h at room temperature. The reaction is treated with excess concentrated hydrochloric acid resulting in a precipitate. The precipitate is filtered to give the title compound. ESI MS m/z 260.1 [M−H]−.
Reaction SMILES: COC([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#C)=[O:14])[CH2:7][CH2:6]1)=O.C[CH2:31][O:32][C:33]([CH3:35])=[O:34].CO>[Pd]>[CH3:31][O:32][C:33]([CH2:35][CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:14])[CH2:7][CH2:6]1)=[O:34]
Reactant: CCOC(C)=O
Reactant: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)OC)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-methoxycarbonylmethylidenyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (29.2 mg, 0.074 mmol) in a mixture of EtOAc/methanol (5 mL/5 mL) was added Pd/C (10%) (32 mg) and the reaction mixture was shaken under 50 psi of H2 for 16 h. The mixture was filtered through a plug of celite, concentrated and the residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 2.25/8.0 to 3.6/7.0 mL/min) to give the separated isomers of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][O:29]C3CCCCO3)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][OH:29])[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CCC(CCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example (11.5) using 4-(3,4-dichloro-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-(3,4,5-trimethoxy-benzyl)-pyrrolidine (3 mmol) and p-toluenesulfonic acid (200 mg). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[CH3:2].[OH-].[Na+].[S:24](=[O:28])(=O)(O)[OH:25]>>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[S:24]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:28])=[O:25])[CH3:21]
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
5.67 g (20 mmol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal (1) obtained in Example 3 was dissolved in 40 ml of 6N sulfuric acid. After stirring at 76°-7° C. for 1.5 hours, the reaction mixture was cooled and the pH was controlled to about 11 by adding 25% aqueous solution of sodium hydroxide at a temperature lower than 30° C. It was extracted with 35 ml and then 10 ml of methylene chloride successively, which were combined and washed with 20 ml of water and then dried over anhydrous magnesium sulfate. The solvent was concentrated under vacuum, the residue was dissolved under heating by adding 12 ml of ethanol and then cooled to 5° C. to deposit crystals. The crystals were collected by filtration, washed with 3 ml of cold ethanol and then dried under vacuum to obtain 3.71 g (yield 78%) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (2), m.p. 152°-3° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:24])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][C:16](=[O:18])[C:15]([C:19](=O)[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]2)=[CH:8][CH:7]=1)[CH3:2].[CH2:25]([O:27][NH2:28])[CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([O:27][N:28]=[C:19]([C:15]1[C:16](=[O:18])[CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[S:24])=[CH:11][CH:10]=2)[CH2:13][C:14]=1[OH:23])[CH2:20][CH3:21])[CH3:26]
Reactant: CCON
Reactant: CCNC(=S)Nc1ccc(C2CC(=O)C(C(=O)CC)=C(O)C2)cc1
Solvent: ClC(Cl)Cl
Product: CCNC(=S)Nc1ccc(C2CC(=O)C(C(CC)=NOCC)=C(O)C2)cc1
Reaction time: 15 h
Yield: 88.9 %

Procedure:
Into 10 ml of chloroform was dissolved 1.4 g of 5-{4-[3-(ethyl)thioureido]phenyl}-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 1.0 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and the reacting mixture was washed with a dilute hydrochloric acid solution and water. The solution was dried with anhydrous magnesium sulfate and the chloroform was distilled off from it under reduced pressure and 1.4 g of the desired compound was obtained. It was in the form of colorless crystals having a decomposition point of 116°-118° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1>CO.CCOC(C)=O.[Pd]>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C=C(C)c1cc(CN)cc(NC(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Nc1cc(CN)cc(C(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of about 92 mg of crude methyl 3-(aminomethyl)-5-(prop-1-en-2-yl)phenylcarbamate and 17.6 mg of 10% Pd/C in 7 mL of MeOH and 2 mL of EtOAc was stirred at r.t. under H2 balloon for 16 h. The mixture was filtered through Celite and concentrated to give the amine product which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:5]=[N:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[N:7]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: N#Cc1cccc(COc2cncc(Cl)n2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(COc2cncc(N3CCNCC3)n2)c1
Temperature: 90 °C
Yield: 22.4 %

Procedure:
A mixture of 3-(6-chloro-pyrazin-2-yloxymethyl)-benzonitrile I-3f (667.2 mg, 2.716 mmol), piperazine (297 mg, 3.531 mmol), sodium t-butoxide (287 mg, 2.987 mmol), BINAP (67.7 mg, 0.109 mmol), and Pd2(dba)3 (49.7 mg, 0.054 mmol) in toluene (10 mL) was heated at 90° C. overnight. The solution was cooled to room temperature and filtered through a celite pad. The celite pad was washed with ethyl acetate several times. The combined filtrate was concentrated in vacuo to give the crude title compound. The product was purified by chromatography (silica, 10% MeOH/dichlormethane with 1% NH4OH) to give 180 mg 3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yloxymethyl)-benzonitrile (3-E).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:20].[OH-].[NH4+]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:20])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(-c2ccnc3c(C#N)cnn23)c1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc(-c2ccnc3c(C(N)=O)cnn23)c1

Procedure:
A mixture of 7-(3-methylphenyl)pyrazolo[1,5-a]-pyrimidine-3-carbonitrile (prepared as described in Example 7 of U.S. Pat. No. 4,236,005) and concentrated sulfuric acid is stirred at room temperature for 16 hours. The solution is then carefully poured into ice with stirring and mixture is carefully made just basic with concentrated ammonium hydroxide. The solid is collected by filtration to give 7-(3-methylphenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[CH3:18][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1-c1cccc(S(C)(=O)=O)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(S(C)(=O)=O)c1
Yield: 63 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-5-methyl-4-(3-(methylsulfonyl)phenyl)pyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 63% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.23 (s, 1H), 8.03 (d, 1H, J=7.8 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.70 (t, 1H, J=7.8 Hz), 7.56 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 3.09 (s, 3H), 2.43 (bs, 8H), 2.26 (s, 6H). MS (ESI): 452.3 [M+H]+, 226.8 [M+2H]2+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[CH:4]=1.[C:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1)(=[O:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:27]/[C:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)=[O:28])=[C:5]([O:16][CH2:17][C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])[CH:4]=1
Reactant: COc1cc(OCC(=O)N2CCOCC2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OCC(=O)N2CCOCC2)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 70 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-72A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Orange solid, mp 231–233° C., 70% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.28–8.35 (m, 3H), 8.21 (s, 1H), 8.07–8.11 (m, 3H), 7.66 (d, 1H, J=3.3 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.87 (s, 1H), 5.13 (s, 2H), 4.00 (s, 3H), 3.65 (brm, 4H), 3.54–3.55 (m, 4H). MS (EI) m/z=507 ([M]+, 100%). Anal. Calcd. for C27H25NO7S.½EtOH: C, 63.55; H, 5.61; N, 2.60; S, 5.95. Found: C, 63.13; H, 5.55; N, 2.53; S, 5.84.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:26][CH2:27]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(c4ccncc4)CC3)cc21
Temperature: 125 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A mixture of 0.31 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.33 g of (4-pyridyl)piperazine and 2 ml of pyridine was stirred at 125° C. for 1 hour. After cooling, the reaction mixture was added to ice water to cause crystallization. The resulting crystal was collected by filtration, washed with ethyl ether and then recrystallized from ethanol to yield 0.1 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:29](=[O:30])[CH2:28][Cl:27])[CH:9]=2)=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNc1ccc(Oc2ccnc(NC(=O)CCl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine (1 eq) and triethylamine (2 eq) in tetrahydrofuran was treated with 2-chloroacetyl chloride and stirred for 15 minutes at room temperature. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuum to give crude product. Purification on silica gel with 2% methanol in methylene chloride gave N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide as a bright orange solid. HPLC=3.82 min; MS: MH+=337.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[OH-].[K+]>C(O)C.O>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:6]1[CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:9]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-II) in ethanol was added potassium hydroxide in water and stirred overnight at room temperature. Solvent was removed under reduced pressure; the residue was taken in water and washed with diethyl ether. The aqueous layer was acidified with dilute HCl and precipitate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated to afford 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid (D1-III).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([S:25]([N:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([S:25]([N:28]2[CH:29]=[CH:30][C:31]([C:10]([C:9]3[CH:13]=[CH:14][C:6]([Cl:5])=[C:7]([S:15]([NH2:16])(=[O:18])=[O:17])[CH:8]=3)=[O:11])=[CH:32]2)(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a suspension of aluminum chloride (1.89 g, 14 mmol) in methylene chloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (2 g, 7.9 mmol). The reaction mixture is stirred at room temperature for 10 minutes then a solution of 1-benzenesulfonyl-1H-pyrrole (1.13 g, 5.45 mmol) in methylene chloride (3.3 mL) is added. After stirring at room temperature overnight, the reaction is quenched with 6 N HCl and extracted with ethyl acetate three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 2:8) provides 0.6 g (26%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 8.30 (s, 1H), 8.15 (m, 2H), 8.05 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.40 (m, 1H), 6.70 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-])=O)=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[ClH:23]>[C].[Pt].C1(C)C=CC=CC=1>[ClH:23].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([NH:12][CH3:13])[C:10]=1[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNc1cccc(OCc2ccccc2)c1N
Reaction time: 0.5 h
Yield: 85 %

Procedure:
0.80 g of 5% platinum carbon (dry) was added to a toluene (80 mL) suspension of 3-benzyloxy-N-methyl-2-nitroaniline (7.19 g, 27.8 mmol), and catalytic hydrogenation reaction was performed under ordinary pressure. The reaction solution was filtered to remove a catalyst, and the catalyst was washed with toluene (10 mL). The washing liquid was added to the precedent filtrate. A 1N hydrochloric acid ethanol solution (28 mL, 28.0 mmol) was added to the mixture under ice cooling, and the mixture was stirred under the same temperature for 30 minutes. The solvent was distilled off under reduced pressure at 20° C. or less. Precipitated crystals were collected by filtration, washed with toluene (15 mL), and dried at 40° C., thereby obtaining 6.30 g of an orange, crystal target compound (yield: 85%).
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N)(C)(C)C.S(N)(N)(=O)=O.C(C1C=CN=NC=1C(CC(C)(C)C)(C)C)(CC(C)(C)C)(C)C.C(N=[N:47][C:48]([CH2:51][C:52](C)(C)C)([CH3:50])[CH3:49])(C)(C)C.C(N=NC(C)(C)C)(C)(C)C>>[C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:48]([NH2:47])([CH2:51][CH3:52])([CH3:50])[CH3:49]
Reactant: CC(C)(C)CC(C)(C)N=NC(C)(C)C
Agent: CC(C)(C)CC(C)(C)N
Agent: CC(C)(C)CC(C)(C)c1ccnnc1C(C)(C)CC(C)(C)C
Agent: CC(C)(C)N=NC(C)(C)C
Solvent: CC(C)(C)N
Product: CCC(C)(C)N

Procedure:
Mixtures of an unsymmetrical azoalkane and the corresponding symmetrical azoalkanes have unique thermal and initiator properties that may extend over a wide temperature range depending upon the R and R' groups. For example, when tert-octylamine (1,1,3,3-tetramethylbutylamine) and tert-butylamine are used in the sulfamide reaction, a mixture of di-tert-octyldiazine (which has a ten hour half life (t-1/2) of 107° C.) and tert butyl tert-octyldiazene (which has a 10 hour half life of 137° C.) is obtained; the 10 hour half lives were extrapolated from data in J. W. Timberlake et al 1976 publication in the Journal of Organic Chemistry, vol 41, page 1666. Di-tert-butyldiazene (which has a 10 hour t-1/2 about 160° C. and a b.p. of 109° C.) is removed during the workup. Mixtures of tert-octylamine with tert-amylamine or tert-dodecylamine (Primene 81-R product) give mixtures of azoalkanes with similar half lives as above. Mixtures of initiators of various activities are commonly used in various polymerization processes. Mixtures of peroxides of different half lives are used in the polymerization of styrene, vinyl chloride, and ethylene. Mixtures of azonitriles are also used in polymerizations but these leave toxic residues in the polymers. Mixtures of azoalkanes derived from tert-octylamine and another tertiary alkyl primary amine are particularly useful where a low or intermediate temperature initiator is required to initiate the polymerization at a reasonable rate and a higher temperature initiator is required to finish the reaction. This is especially true in the bulk polymerization of styrene where a high temperature initiator is required to obtain faster conversion to polystyrene. Peroxides cannot be used in this capacity because they degrade polystyrene at the higher temperatures. Azonitriles are too unstable to be used as finishing catalysts. In fact, prior to our invention, no such suitable commercially feasible initiator system existed.