Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[C:14]([OH:17])(=[O:16])[CH3:15]>C(O)C>[C:14]([O-:17])(=[O:16])[CH3:15].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: CC(=O)O
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CCO
Product: CC(=O)[O-]
Product: CO[Si](CCC[NH+](C)C)(OC)OC

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 24 g of ethanol were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 1.5 g of acetic acid was dissolved in 24 g of ethanol was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for half a day and therefrom, ethanol was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and acetic acid as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in ethanol to obtain a 13.1% ethanol solution of trimethoxysilylpropyldimethylammonium acetate.
Reaction SMILES: C(O)(O)CCCCC.C(Br)CCCCCCC.C(OCCCCCCOC(C)=O)CCCCCCC.[C:37]([O:62][C:63]([C:66]([C:69]([C:72]([C:75](C(O)=O)([F:77])[F:76])([F:74])[F:73])([F:71])[F:70])([F:68])[F:67])([F:65])[F:64])([C:40]([C:43]([C:46]([C:49]([C:52]([C:55]([C:58]([F:61])([F:60])[F:59])([F:57])[F:56])([F:54])[F:53])([F:51])[F:50])([F:48])[F:47])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38]>>[C:37]([O:62][C:63]([C:66]([C:69]([C:72]([CH:75]([F:76])[F:77])([F:73])[F:74])([F:70])[F:71])([F:67])[F:68])([F:65])[F:64])([C:40]([C:43]([C:46]([C:49]([C:52]([C:55]([C:58]([F:61])([F:60])[F:59])([F:57])[F:56])([F:54])[F:53])([F:51])[F:50])([F:48])[F:47])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCCCC(O)O
Agent: CCCCCCCCOCCCCCCOC(C)=O
Solvent: CCCCCCCCBr
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 185 °C

Procedure:
In a fashion similar to Example 8, hexanediol was alkylated with n-octyl bromide, the product was acetylated, and the resulting C8H17—O—(CH2)6—O—COCH3 was directly fluorinated and hydrolyzed as in Example 8 to C8F17—O—(CF2)5COOH, which was recrystallized from perfluorohexane. The recrystallized acid (37.5 g) was mixed with 4.0 g NaOH and 100 mL ethylene glycol and heated to 185° C. The product was washed with water, and the residual 27.9 g was distilled to give pure C8F17—O—(CF2)5H, micro b.p. 195° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([NH2:12])=[CH:7][N:6]=1>CO.CCOC(C)=O>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([NH2:12])=[CH:7][N:6]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
Sodium methoxide (0.5M in methanol, 3.7 mL, 1.829 mmol) was added to a solution of 2,4-dichloropyrimidin-5-amine (0.2 g, 1.220 mmol) in MeOH (2.5 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title product as a brown solid (177 mg, 91%). 1H NMR (500 MHz, CDCl3): δ 3.93 (s, 3H), 5.31 (br s, 2H), 7.73 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.6 min, 160 [M+H]+
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[C:6]2[N:7]([N:12]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:20][CH:21]=3)[N:14]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC>[CH3:3][O:4][C:5]1[C:6]2[N:7]([N:12]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]([CH3:28])[CH:21]=3)[N:14]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C)n2nc(CCc3c[nH]c(-c4ccccc4)n3)nc12
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc(C)n2nc(CCc3cn(C)c(-c4ccccc4)n3)nc12
Temperature: 50 °C

Procedure:
Methyl iodide (0.035 mL, 0.57 mmol) was added to a stirred suspension of 8-Methoxy-5-methyl-2-[2-(2-phenyl-1H-imidazol-4-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (145 mg, 0.435 mmol) and Cs2CO3 (360 mg, 1.1 mmol) in 2-Butanone (10 mL). The mixture was heated at 50° C. for 7 hours under an atmosphere of Argon. The mixture was cooled to rt and the solvent was evaporated off. The crude product was dissolved in DCM and purified by silica gel chromatography (Eluent: 0-100% EtOAc in n-heptane, then changed to 0-5% MeOH in EtOAc). Yield: 31 mg (20%) of the title compound as an off white solid. LC-MS: m/z=348.2 (MH+), tR=0.70 min, method E.
Reaction SMILES: [C:1]([NH:4][S:5](=[O:16])([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([NH2:14])=[C:9]([Br:15])[CH:8]=1)=[O:6])(=O)[CH3:2].P(Cl)(Cl)([Cl:19])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:14][C:10]1[C:11]([Br:13])=[CH:12][C:7]([S:5]([N:4]=[C:1]([Cl:19])[CH3:2])(=[O:16])=[O:6])=[CH:8][C:9]=1[Br:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(Cl)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1

Procedure:
A mixture of 372 mg. of N1 -acetyl-3,5 dibromo sulfanilamide, 7.5 ml. of benzene, 5 ml. of phosphorous oxychloride and 230 mg. of phosphorous pentachloride is refluxed for 2 hours. The reaction mixture is cooled and concentrated in vacuo to an oil which solidified upon trituration with hexane. The solid material is filtered and washed with hexane affording N-(4-amino-3,5-dibromophenylsulfonyl) acetimidoyl chloride, which is used without further purification in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][N:4]1[C:10](=[O:11])[CH2:9][C:8]2[CH:12]=[CH:13][CH2:14][CH2:15][C:7]=2[CH2:6][CH2:5]1.[OH:17][N:18]=C1C2C=CCCC=2CCN(C)C1=O>>[OH:17][N:18]=[C:9]1[C:8]2[CH:12]=[CH:13][CH2:14][CH2:15][C:7]=2[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:10]1=[O:11]
Reactant: CN1CCC2=C(C=CCC2)C(=NO)C1=O
Reactant: CC(C)CN1CCC2=C(C=CCC2)CC1=O
Product: CC(C)CN1CCC2=C(C=CCC2)C(=NO)C1=O

Procedure:
Following the procedure described for Example 7-A (Step B) and using 3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one, 1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:41]1([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:48]3[CH2:49][CH2:50][CH2:51][CH:47]3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCCC1c1ccccc1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 30 mg of 1-(4-chlorophenyl)cyclopropanecarboxylic acid and 81 mg BOP reagent in 0.5 mL methylene chloride wad added 27 mg of 2-phenylpyrrolidine, followed by the addition of 53 ul of Hunig base. The reaction mixture was stirred at r.t. for 2 hours and directly purified by flash column using ethyl/hexane as the eluting solvent to provide the desired 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2-phenylpyrrolidine. LCMS (ESI): 326.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:22]1([S:32]([O-:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.[Na+]>>[C:22]1([S:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1cccc2ccccc12
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc5ccccc45)cc3c2C1
Yield: 26 %

Procedure:
The product of Example 29, step B and sodium 1-naphthylsulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) provided tert-butyl 8-(1-naphthylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (76 mg, 26%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.67 (d, J=8.1 Hz, 1H), 8.51 (dd, J=7.5, 1.2 Hz, 1H), 8.18-8.01 (m, 2H), 7.92-7.76 (m, 2H), 7.67-7.41 (m, 4H), 4.58-4.47 (m, 2H), 3.81 (br s, 2H), 2.83 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C(=O)[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].[C:31](=[O:34])([O-])O.[Na+]>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:31](=[O:34])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1c(O)c2ccccc2n(-c2ccccc2)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2ccccc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-phenylacetyl-quinolin-2(1H)-one (255 mg, 0.72 mmol) produced in Synthesis Example 13 in DMF (7 mL) was added hydrazine monohydrate (purity of 80%, 0.12 mL), and the mixture was stirred at 100 to 110° C. for 4 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c]quinolin-4(5H)-one as a form of crystal (177 mg, yield 70%).
Reaction SMILES: [H-].[Na+].C[C:4]1(C)[C:13]2C(=CC=C(C#CC3C=CC(C([O-])=O)=CC=3)[CH:12]=2)N[C:6](=O)[CH2:5]1.ICCCCCCC.[CH3:35][C:36]1([CH3:63])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=3)[CH:44]=2)[N:39]([CH:59](C)[CH3:60])[C:38](=[O:62])[CH2:37]1>CN(C=O)C>[CH3:63][C:36]1([CH3:35])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=3)[CH:44]=2)[N:39]([CH2:59][CH2:60][CH2:6][CH2:5][CH2:4][CH2:13][CH3:12])[C:38](=[O:62])[CH2:37]1
Reactant: CC1(C)CC(=O)Nc2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(=O)N3C(C)C)cc1
Agent: CCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21

Procedure:
NaH (98.4 mg, 2.7 mmol), ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl )ethynyl]benzoate (Compound 4, 635 mg, 1.8 mmol) and iodo heptane (2.73 mL, 18 mmol) in 3 mL of DMF were reacted substantially in accordance with the procedure used for the preparation of ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-iso-propyl-6-quinolinyl)ethynyl]benzoate (Compound 5), to give the title compound as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[Na+].[I-]>C(#N)C.O>[C:17]([O:16][C:14](=[O:15])[CH2:13][N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH2:8]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Brc1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-bromo-1,2,3,4-tetrahydro-isoquinoline (10.60 g, 50 mmol) and t-butyl bromoacetate (9.95 g, 51 mmol, 1.02 eq.) in acetonitrile (100 ml) are added sodium carbonate (10.6 g, 100 mmol, 2.0 eq.) and NaI (375 mg, 2.5 mmol, 0.05 eq.). The resulting mixture is stirred at rt for 16 hr. Water (100 ml) is added to quench the reaction, and the acetonitrile is evaporated. The residue is extracted with EtOAc (100 ml×3), and the combined organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel flash chromatography (EtOAc/hexane, 1:4) to give the title compound. MS (+VE) m/z 326.10 (M++1).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9].C[O-].[Na+].Cl>O>[CH3:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8]([O:3][CH2:2][CH2:1][OH:4])=[O:9]
Reactant: CCOC(=O)CN(C)c1ccccc1
Reactant: OCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)OCCO)c1ccccc1
Temperature: 150 °C
Reaction time: 13 h

Procedure:
Into a 100 ml. flask fitted with a condenser and a Dean-Stark trap there were placed 49.5 gms. ethylene glycol, 17 gms. of ethyl N-methyl-N-phenylglycinate and 0.7 gm. sodium methoxide. The flask and contents were heated to 150° C. in an oil bath and stirred for 13 hours. The reaction mixture was allowed to cool to room temperature and 1.25 ml. of concentrated HCl in 3.5 ml. water were added and the mixture was stirred for 10 minutes. After the ethylene glycol was distilled off at atmospheric pressure, 11.5 gms. of product was obtained by vacuum distillation, b.p. (0.3 mm.) 139°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.ClC1C=C([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1C
Product: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Yield: 50 %

Procedure:
2-Chloro-8-methyl-7-methoxy-4-(4-methoxy-benzyloxy)-quinoline 221b was synthesized from compound 220b as a white powder in 50% yield, following the procedure as described for compound 221d. 1H NMR (CDCl3, 376 MHz) δ (ppm) 2.60 (s, 3H), 3.85 (s, 314), 3.97 (s, 3H), 5.18 (s, 2H), 6.69 (s, 1H), 6.97 (d, J=8.57 Hz, 1H), 7.19 (d, J=8.57 Hz, 1H), 7.42 (d, J=8.57 Hz, 1H), 8.02 (d, J=8.57 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([S:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)=[O:14])(C(C)(C)C)(C)C.Cl>CCOCC.O>[Cl:30][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([Cl:31])[C:24]=1[S:23][C:17]1[S:16][C:15]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][OH:8])=[O:14])=[CH:19][C:18]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C(NCCCO)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamide (1.0 g, 1.92 mmol) from the above was added to a solution of hydrogen chloride in ether (2.0 M, 15 mL) and dry ether (15 mL), and the resulting mixture was stirred at ambient temperature for 1 hour. After this time, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 97:3 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (550 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, s), 8.81 (1H, m), 8.43 (1H, s), 3.41 (2H, m), 3.24 (2H, m), 1.61 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.OO.[ClH:13]>>[NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cl
Reactant: Nc1nc2ccccc2[nH]1
Agent: OO
Product: Nc1nc2ccc(Cl)cc2[nH]1
Yield: 72 %

Procedure:
Commercial 2-aminobenzimidazole was chlorinated with a mixture of hydrogen peroxide and HCl in aqueous solution at rt for 1.5 h. After removal of all volatiles the residue was dissolved in water and the product precipitated by addition of ammonia solution to give a 72% yield of 2-amino-5-chlorobenzimidazole as beige coloured solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([O:15][P:16]([C:21]([NH2:24])([CH3:23])[CH3:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(#N)C>[CH2:18]([O:17][P:16]([C:21]([NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:22])[CH3:23])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: CCOP(=O)(OCC)C(C)(C)N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)C(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
83 g of 3-nitrobenzoyl chloride in 150 ml of acetonitrile are added dropwise to a solution of 105 g of 2-aminopropane-2-phosphonic acid diethyl ester and 45 g of triethylamine in 300 ml of acetonitrile at 0° C, with good stirring. After completion of the addition, the mixture is stirred for a further 3 hours at 0° C; it is then filtered and the solvent is distilled off in vacuo. The residue is purified by extraction by shaking with ether and aqueous 2 normal sodium carbonate solution. 99 g of 2-(3'-nitrobenzamido)propane-2-phosphonic acid diethyl ester of melting point 95°-96° C are obtained. This product is reduced with hydrogen as indicated in Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([Cl:26])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)Cl)C(F)(F)F
Yield: 91.9 %

Procedure:
A solution of (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid (414 mg.), thionyl chloride (1.0 g.) and dimethylformamide (0.05 g.) in benzene (10 ml.) is heated under reflux for 1 hour. The solvent is evaporated in vacuo, and light petroleum (10 ml., b.p. 60°-80° C.) is added, and the mixture is re-evaporated. A further 10 ml. of light petroleum are added, and the mixture re-evaporated. The residue is dissolved in light petroleum, and the solution is filtered and evaporated to give (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionyl chloride (401 mg.).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C.O.O.O.[Os](Cl)(Cl)Cl.O>[C:6]([O:9][CH:4]1[NH:1][C:2](=[O:5])[CH2:3]1)(=[O:8])[CH3:7]
Reactant: O=C1CCN1
Reactant: CC(=O)[O-]
Agent: Cl[Os](Cl)Cl
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1CC(=O)N1
Yield: 78.6 %

Procedure:
To a mixture of 200 mg (2.8 mmole) of azetidin-2-one, 230 mg (2.8 mmole) of anhydrous sodium acetate, 2 ml of acetic acid, and 17 mg (2 mole % based on the amount of azetidin-2-one) of osmium trichloride trihydrate was added dropwise, with stirring, 1.56 g (6.2 mmole) of a 30% peracetic acid solution in ethyl acetate at room temperature over a period of 2 hours or more. The reaction mixture was poured into 50 ml of water and extracted with n-hexane. The extract was separated and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1 by volume). Thus, 280 mg (2.2 mmole, percent yield: 78%) of 4-acetoxyazetidin-2-one in a colorless oily state was obtained.
Reaction SMILES: [NH2:1][C:2]([N:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>CN(C)C=O>[NH2:1][C:2]([N:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: CN(C)C(N)=C(C#N)C#N
Reactant: S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(N)=C(C#N)C(N)=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 5.4 g of 3-amino-2-cyano-3-(dimethylamino)propenenitrile and 4.0 g of triethylamine in 25 ml of dimethylformamide at 50° were added 11.6 g of aqueous hydrogen sulfide. Upon complete addition of hydrogen sulfide, the reaction mixture was heated at 65° for 1 hour. Since comparison by thin-layer chromatography of the reaction mixture with the starting material indicated that no reaction had taken place, the reaction temperature was increased to 80°, where it was maintained for two hours, but again no reaction occurred. A small amount of triethylamine and 1 g of hydrogen sulfide were added to the solution. Heating was then continued at 85°. After 30 minutes reaction (as determined by thin-layer chromatography) was 40% complete. Small increments of triethylamine and hydrogen sulfide were added as heating continued until, after 21/2 hours at 85°, reaction was 95% complete. The solution was poured onto 150 ml of ice-water, and was purged with nitrogen gas to remove excess hydrogen sulfide. After 30 minutes, a solid formed, and was collected by filtration. The solid filter cake was washed with cold water and air-dried overnight to give 4.6 g of white solid 3-amino-2-cyano-3-(dimethylamino)propenethioamide, m.p. 186°-187° . The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1([Cl:22])[CH2:4][C:3]1([CH2:6][S:7][C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=2[CH:9]=1)[CH3:5].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:22][C:2]1([Cl:1])[CH2:4][C:3]1([CH2:6][S:7]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=2[CH:9]=1)=[O:28])[CH3:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2cc(SCC3(C)CC3(Cl)Cl)ccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(S(=O)CC3(C)CC3(Cl)Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of 7.2 g (0.2 mole) of [5-[[(2,2-dichloro-1-methylcyclopropyl)methyl]thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 120 ml of CHCl3 and 120 ml of acetic acid at -15° C there is added 4.2 g (0.02 mole) of 85% m-chloroperoxybenzoic acid and 40 ml of CHCl3 and with stirring is allowed to warm to room temperature. The mixture is stirred for an additional 2 hours. The CHCl3 is removed in vacuo and the remaining solution is neutralized with aqueous NaHCO3. The resulting solid is filtered off, dried, and crystallized from acetonitrile to yield 3.4 g of the title compound, m.p. 231-233° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=3[CH3:20])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:23][NH2:24].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[CH3:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([N:10]1[CH2:9][CH2:8][C:5]2[N:6]=[N:7][C:2]([NH:23][NH2:24])=[CH:3][C:4]=2[CH2:11]1)=[O:21]
Reactant: NN
Reactant: Cc1cccc(C(=O)N2CCc3nnc(Cl)cc3C2)c1C
Agent: O=C(O)c1cc(O)ccc1O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)N2CCc3nnc(NN)cc3C2)c1C

Procedure:
10.3 g of 3-chloro-6-(2,3-dimethylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate in 80 cc of dioxane are heated in an oil bath of 80°. After a reaction time of 60 hours, the mixture is concentrated in a vacuum, the oily residue is divided between 250 cc of chloroform and 150 cc of water, and after concentrating the chloroform phase, the resulting oily crude base is reacted with gentisic acid as described in Example 10. The gentisinate of the title compound has a M.P. of 176°-179° (decomp.) after recrystallization from 150 cc of methanol and 100 cc of water.