Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Br.O1CCCC1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C1=CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
600 mL of 0.5 M o-tolylmagnesium bromide-tetrahydrofuran solution was cooled to 0° C., and 200 mL of tetrahydrofuran solution of 40.0 g of 1-benzylpiperidin-4-one was dropwise added thereto, over 10 minutes. Cooled with ice, the reaction mixture was stirred further for 30 minutes. Then, aqueous saturated ammonium chloride solution was added thereto to stop the reaction, and this was extracted three times with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. 300 mL of trifluoroacetic acid was added to the resulting residue, heated up to 80° C., and stirred for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was neutralized with aqueous saturated sodium hydrogencarbonate solution, and then extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=20/1 to 10/1) to obtain 39.9 g of the entitled compound as a pale brown oily substance.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH2:11][CH:10]([CH2:12][NH2:13])[C:8]3=[CH:9][C:4]=2[O:3][CH2:2]1.O.[OH-].[Na+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[NH:13][CH2:12][CH:10]1[C:8]2=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=[C:7]2[CH2:11]1)[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: NCC1Cc2cc3c(cc21)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NCC1Cc2cc3c(cc21)OCO3
Reaction time: 2 h

Procedure:
7.9 g (44.6 mmoles) of (5,6-dihydrocyclobuta[4,5]benzo[1,2-d][1,3]dioxol-5-ylmethyl)amine are dissolved in 80 mL of dichloromethane. 80 mL of water and 6 mL (1.6 equivalents) of (12N) aqueous sodium hydroxide solution are added. Over 15 minutes there are added 3.95 mL (1.1 equivalents) of ethyl chloroformate and stirring is carried out at 25° C. for 2 hours. The mixture is separated and the organic phases is washed with saturated aqueous NaHCO3 solution. Drying over MgSO4, filtration and evaporation to dryness are carried out. The expected product is obtained in the form of a brown solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([F:30])[CH:19]=3)[CH3:17])[N:15]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].[H-]>O1CCCC1>[F:30][C:20]1[CH:19]=[C:18]([CH:16]([C:14]2[N:15]=[C:11]([NH:10][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:12][CH:13]=2)[CH3:17])[CH:23]=[CH:22][C:21]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)Cc2ccccc2)n1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NCCc2ccccc2)n1
Yield: 49.9 %

Procedure:
To 2-phenylacetamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (1.00 g, 2.51 mmol) in tetrahydrofuran (20 ml) was added lithium aluminu hydride (150 mg) by portion, then the mixture was refluxed for 2 hr. After cooling, the reaction mixture was filterated and evaporated under reduced pressure to a residue. The residue was extracted with chloroform and the extracts were washed with water, dried, then evaporated under reduced pressure to a residue, which chromatographed and recrystallized to afford 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-phenethylaminothiazole (504 mg, 50% yield): mp 74.5°-75.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][N:3]=1.[C:16]([NH2:19])(=[O:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.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]>[Cl:15][C:11]1[CH:10]=[C:9]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH:19][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Oc2cnc(Br)cn2)ccn1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc(Oc2ccnc(Cl)c2)cn1
Temperature: 80 °C
Yield: 31.6 %

Procedure:
A solution of 2-bromo-5-((2-chloropyridin-4-yl)oxy)pyrazine (1.2 g, 4.19 mmol) in dioxane (20 mL) was degassed, treated with acetamide (0.495 g, 8.38 mmol), Cs2CO3 (2.05 g, 6.28 mmol), X-Phos (0.200 g, 0.419 mmol) and Pd2(dba)3 (0.192 g, 0.209 mmol) and heated at 80° C. for 3 h. The mixture was cooled to RT and diluted with EtOAc. The solids were removed via filtration through diatomaceous earth, rinsed well with EtOAc, and the filtrate washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-chloropyridin-4-yl)oxy)pyrazin-2-yl)acetamide (0.35 g, 31%). MS (ESI) m/z: 265.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(I)ccc1F
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step 3 starting from 2-Fluoro-5-iodo-benzonitrile (1.0 g, 4.14 mmol), and Ethynyl-trimethyl-silane (0.487 g, 4.97 mmol), and was obtained as a waxy brown solid, (0.90 g, 99%), identified by NMR and mass spectral analyses. MS (EI+): 216 (M+).
Reaction SMILES: [F-:1].[K+].CC(CC(O)CO)C.[Cl:11][C:12]1[CH:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15].C1(C)C(C)=CC=CC=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:12]1[CH:19]=[C:18]([F:1])[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(F)c(Cl)cc1Cl
Reactant: [F-]
Agent: CC(C)CC(O)CO
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: N#Cc1cc(F)c(F)cc1Cl
Temperature: 130 °C
Reaction time: 8 h

Procedure:
In a 100 ml flange flask fitted with a distillation bridge and anchor stirrer, 14.5 g (0.25 mol) of potassium fluoride, 4.8 g (0.007 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride, 6.2 g (0.012 mol) of polyethylene glycol dimethyl ether 500 and 2.4 g (0.007 mol) of tetrabutylphosphonium bromide were introduced at 100° C. into the melt of 47.5 g (0.25 mol) of 2,4-dichloro-5-fluorobenzonitrile. Subsequently, 10 g (0.09 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 20 mbar and heating to 130° C. After the xylene had been distilled off, the reaction suspension was heated to 140° C. and stirred for 8 hours at this temperature. Amount of 2-chloro-4,5-difluorobenzonitrile formed:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:38][CH2:39][CH2:40][CH3:41])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=O)[CH:28]=2)=[C:21]([O:36][CH3:37])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1>[CH2:38]([N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=[CH:5][C:3]#[N:4])[CH:28]=2)=[C:21]([O:36][CH3:37])[CH:20]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=O)CC(C)(C)C2)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC#N)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 0.23 g (9.6 mmol) of sodium hydride, 20 ml of tetrahydrofuran was added. To this mixture, 1.39 g (7.85 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling. To the mixture, 1.21 g (3.15 mmol) of 3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenone in tetrahydrofuran was added dropwise. After the reaction mixture was stirred at 50° C. overnight, water was added thereto and extraction with ethyl acetate was performed. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 1.05 g of an orange oily matter (yield: 82.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]2)=[CH:5][CH:4]=1.[NH3:20]>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH2:20])=[O:15])[CH2:9]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Product: COc1ccc(CN2CC(C(N)=O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of methyl 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate (65.8 g, 250 mmol) and aqueous ammonia (1.5 L) was stirred at room temperature overnight. The resulting reaction mixture was filtered. The filter cake was washed with H2O several times and dried in vacuo to afford 1-(4-methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic acid amide as a white solid (60.0 g, yield: 96.5%).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16]>>[NH2:20][C:18]1[N:17]=[C:15]([NH2:16])[C:12]2[CH2:13][CH:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10][C:11]=2[N:19]=1
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: N#CNC(=N)N
Product: Nc1nc(N)c2c(n1)CCC(Cc1ccccc1)C2

Procedure:
For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOCC>O1CCCC1>[OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([O:11][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:10]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12

Procedure:
3-Hydroxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (500 mg.) was dissolved in dry tetrahydrofuran and treated with a solution of diphenyldiazomethane (300 mg., 1.1 equiv.) in petrol. Nitrogen was evolved slowly, and after 21/2 hours the solution was evaporated, the residue dissolved in ethyl acetate, and the solution was washed with bicarbonate solution and re-evaporated. This gave a gum which solidified on trituration with ether (0.5 g.). A sample was recrystallised from methanol, m.p. 164°, [α]D23 = + 25° (c, 1.0, dioxan), +22° (c 1.0, tetrahydrofuran). λλmax. ethanol 234 nm. E1 cm1% = 255, (ε = 13,300), 259 nm. E1cm1% = 151 (ε 7,850), νmax. (bromoform) 3420 (OH), 3280 (NH), 1750 (β-lactam), 1722 cm-1 (COOR). (Found, C, 62.2; H, 4.5; N, 5.4; S, 12.1. C27H24N2O5S2 requires C, 62.3; H, 4.7; N, 5.4; S, 12.3%) RF = 0.83 (Kieselgel G plates; ethyl acetate:benzene=1:2).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[C:11](Br)[CH:10]=[C:9]([CH3:14])[N:8]=1)=[O:4].[NH4+].[OH-].CCOC(C)=O.[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:1][C:2]([F:16])([F:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:25]#[N:26])[CH:10]=[C:9]([CH3:14])[N:8]=1)=[O:4]
Reactant: Cc1cc(Br)cc(COC(=O)C(F)(F)F)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(COC(=O)C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1.93 g of (4-bromo-6-methylpyridin-2-yl)methyl 2,2,2-trifluoroacetate in 10 mL of DMF (degassed) was added 667 mg (5.68 mmol) of Zn(CN)2 and 689 mg (0.600 mmol) of Pd(PPh3)4. The mixture was stirred at 80° C. for about 4 h, and 233 mg of Pd(PPh3)4 was added. After 2.5 h, 50 mL of 10% NH4OH solution, and EtOAc were added. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1 to 5) % MeOH/CHCl3 provided 1.20 g of (4-cyano-6-methylpyridin-2-yl)methyl 2,2,2-trifluoroacetate as a yellow solid with some impurity.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:7])[CH2:5][SH:6].[CH3:8][O:9][C:10](=[O:14])[C:11]([Cl:13])=[CH2:12]>O>[CH3:8][O:9][C:10](=[O:14])[CH:11]([Cl:13])[CH2:12][S:6][CH2:5][C:4]([O:3][CH3:2])=[O:7]
Reactant: COC(=O)CS
Reactant: C=C(Cl)C(=O)OC
Agent: [Na]
Solvent: O
Product: COC(=O)CSCC(Cl)C(=O)OC
Yield: 99.6 %

Procedure:
0.076 gram (3.31 mmoles) of metallic sodium were dissolved in 17.97 grams (169 mmoles) of thioglycolic acid methyl ester. This solution was then subsequently under stirring dropped into 20.0 grams (166 mmoles) of freshly distilled 2-chloro-acrylic acid methyl ester dissolved in 30 ml of water free methylene chloride within 1 hour at 25° C. After 4 hours post reaction at 25° C. it was worked up according to Example 1. There were obtained 37.5 grams (99.6% of theory) of 2-chloro-3-methoxycarbonylmethylmercapto-propionic acid methyl ester as a yellowish oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: CN(C)CCO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCOC(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A 391 mg (2.5 mmole) portion of phenyl chloroformate was added dropwise to a solution of 223 mg (2.5 mmole) of N,N-dimethylethanolamine and 253 mg (2.5 mmole) of triethylamine in 5 ml of methylene chloride under ice-cooling with stirring, followed by stirring further under ice-cooling for 10 minutes and then at room temperature for 30 minutes. The reaction solution was diluted with methylene chloride, and the solution was washed with 1% aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was distilled off, and there was obtained 465 mg of the crude 2-dimethylaminoethyl phenyl carbonate in the form of a colorless oil. 880 mg (2.2 mmole) of the compound as obtained in Example 80 was added to the compound, followed by warming at 90° C. for 2 hours. The reaction solution was subjected to separation and purification by chromatography on a column of silica gel (40 g). After impurities were removed with n-hexane-ethyl acetate (1:4) as an eluent, there was obtained the objective compound in the form of a colorless powder from the eluate of chloroform-methanol (10:1). Yield of 800 mg (71%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2]>C(O)C.[Pd]>[CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2]
Reactant: CCNc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccncc1N
Yield: 93.9 %

Procedure:
Ethyl-(3-nitropyridin-4-yl)amine (8.7 g, 52.0 mmol) in ethanol (150 ml) was hydrogenated for 18 hours in the presence of 10% palladium on carbon. After filtration of the catalyst through celite, the filtrate was concentrated in vacuo to afford the title compound (6.7 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]([C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([N+:22]([O-])=O)=[CH:14][C:13]=1[N+:25]([O-])=O)[C:7](=[O:11])[O:8][CH2:9][CH3:10]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]([C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([NH2:22])=[CH:14][C:13]=1[NH2:25])[C:7](=[O:11])[O:8][CH2:9][CH3:10]
Reactant: CCOC(=O)N(Cc1cccc(Cl)c1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N(Cc1cccc(Cl)c1)c1c(N)cc(N)cc1C(F)(F)F
Reaction time: 7 h
Yield: 98.3 %

Procedure:
Ethyl 3-chlorobenzyl[2,4-dinitro-6-(trifluoromethyl)phenyl]carbamate (129.5 mg) was dissolved in ethyl acetate (20 ml), and to the solution was added 10% Pd—C (125.0 mg). The reaction mixture was stirred under hydrogen atmosphere for 7 hours. The catalyst was filtered, and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (110.3 mg).
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29](Cl)(=[O:31])=[O:30])=[C:24]([CH3:33])[C:23]=1[CH3:34])=[O:17])[CH3:14]>CC(C)=O>[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29]([NH:11][C:4](=[NH:12])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:31])=[O:30])=[C:24]([CH3:33])[C:23]=1[CH3:34])=[O:17])[CH3:14]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CCCOc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cc(C)c(S(=O)(=O)NC(=N)c2ccccc2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
1N NaOH (6.43 ml) was added into a mixture of benzamidine hydrochloride (1.00 g) and acetone (25 ml) under ice-water cooling, and then a mixture of 4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenesulfonyl chloride (3.36 g) and acetone (5 ml) was added dropwise thereto over 10 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated by N2 flow to remove the excess of solvents, and was poured into a mixture of water and AcOEt. The separated organic phase was washed with sat. NaHCO3aq., water, and brine, and was dried over MgSO4. After evaporation, the resulting residue was purified by chromatography over silica gel (CHCl3-methanol (MeOH) as eluent) to give N-[4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenesulfonyl]benzamidine (1.39 g) as an oil compound.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[CH3:6].[OH-].[Na+].Cl>CO.O>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][CH2:4][N+:1]([O-:3])=[O:2])[CH:9]=1)[CH3:6]
Reactant: CCOc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cccc(CC[N+](=O)[O-])c1
Temperature: -10 °C
Yield: 37.5 %

Procedure:
A mixture of nitromethane (0.36 mL, 6.7 mmol) and 3-ethoxy-benzaldehyde (1 g, 6.7 mmol) in methanol (1.4 mL) was cooled to −10° C. To this mixture sodium hydroxide (0.28 g in 1 mL water) was added dropwise. The temperature during addition was maintained around 10° C. After 1 hour a yellow precipitate formed and water (5 mL) was added. The resulting solution was added to HCl (4M, 3 mL). The precipitate that formed was filtered off and washed with water. Purification by chromatography on silica, eluting with 1 to 15% ethyl acetate in hexane, gave the subtitled compound as a yellow solid (0.49 g). 1H NMR δ (CDCl3) 1.40-1.48 (3H, t), 4.014.13 (2H, q), 6.97-7.06 (2H, m), 7.09-7.15 (1H, d), 7.30-7.40 (1H, t), 7.53-7.62 (1H, d), 7.91-8.00 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1.C(O)C=C>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:19][CH:14]=[CH2:15])=[O:6]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C=CCO
Product: C=CCOC(=O)c1cc(F)cc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
3-Fluoro-5-nitrobenzoic acid (3 g, 16.2 mM), p-toluene-sulfonic acid (1.54 g, 8.1 mM), and allyl alcohol (50 ml) were heated to reflux, passing the distillate through 3å molecular sieves, for 16 hours. After cooling, the mixture was neutralised with triethylamine, and solvent removed. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, aqueous NaHCO3, and brine, and dried over MgSO4. Crude product was purified by chromatography on silica, using a gradient elution from dichloromethane to ethyl acetate/dichloromethane (3:1), to give allyl 3-fluoro-5-nitrobenzoate. Nmr (CDCl3): δ 4.89 (dt, 2H); 5.33-5.49 (m, 2H); 5.95-6.15 (m, 1H); 8.11 (m, 2H); 8.70 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Clc1c(Br)ccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1c(Br)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a mixture of 5-bromo-4-chloro-1H-indazole (8.0 g, 34.6 mmol) and DHP (8.72 g, 0.104 mol) in dry dichloromethane (200 mL) was added PTSA (0.657 g, 3.46 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Upon completion, saturated aqueous NaHCO3 (100 mL) was added slowly to the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-3% EtOAc in petroleum ether) affording the title compound (8.9 g). 1H NMR (300 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.71 (m, 2H), 5.88 (dd, 1H), 3.89-3.84 (m, 1H), 3.79-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.05-1.95 (m, 2H), 1.75-1.70 (m, 1H), 1.60-1.54 (m, 2H).