Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:9]#[C:10][NH2:11].[C:12](=[O:15])([O-:14])[OH:13].[Na+]>O>[C:12](=[O:13])([OH:15])[OH:14].[C:2]1([NH:1][C:10]([NH2:11])=[NH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: N#CN
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(N)Nc1ccccc1
Product: O=C(O)O
Temperature: 87 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
To 98.2 g aniline (1.0 mol) is added 32% HCl until the pH of the solution reaches approximately 2.5; 95.2 g (0.83 mol) 32% HCl are required. The solution is heated to 87° C. and stirred while 93.0 g of a 50% aqueous solution of cyanamide (1.10 mol) are added over a period of 1 hour. Shortly before completion of the cyanamide addition, another 16.8 g (0.15 mol) 32% HCl are added. After 3 hours stirring at 87° C. the solution is cooled to 60° C. and added to a stirred suspension of 101.0 g (1.20 mol) sodium hydrogencarbonate in 170 ml water at 60° C. After cooling to 5° C., 127.6 g phenylguanidine hydrogencarbonate (dried at 45° C./100 mbar) are isolated (66.8% free base), representing a yield of 94.5% based on aniline. The melting point (decomposition) is 150° to 152° C.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[O:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:32]N1C(=O)CCC1=O>C1COCC1>[Br:32][CH2:2][C:1]([C:4]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[O:8][CH2:9][C:10]([CH3:11])([CH3:12])[C:6]=2[CH:5]=1)=[O:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 5-acetyl-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (2.46 g, 10.0 mmol) in 25 mL of anhydrous THF is added dropwise to lithium diisopropylamide (6.0 mL, 12.0 mmol, 2.0M solution in heptane-THF-ethyl benzene) at -78° C. The resulting solution in stirred at -78° C. for 15 min, and chlorotrimethylsilane (1.5 mL, 12.0 mmol) is introduced. The reaction mixture is stirred at -78° C. for 15 min, warmed to room temperature, stirred for 1.5 h, quenched with water, and extracted with ether. The extract is dried over anhydrous sodium sulfate and concentrated in vacuo; the residue is dissolved in 25 mL of anhydrous THF and reacted at 0° C. with N-bromosuccinimide (1.78 g, 10.0 mmol). The resulting yellowish solution is kept at 0° C. for 0.5 h, warmed to room temperature, stirred for 0.5 h, quenched with water, and extracted with ether. The extract is dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→20% ether-hexane) affords about 2.85 g (88%) of 5-bromoacetyl-7-tert-butyl-2,3-dihydro-3,3-dimethyl-benzo[b]furan as a yellowish solid: mp 54-56° C.
Reaction SMILES: [Si]([O:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([CH2:12][CH2:13][C:14]2=[O:18])[CH2:10]1)(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([CH2:12][CH2:13][C:14]2=[O:18])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CCC(=O)N2C1=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC2CC(O)C(=O)N12

Procedure:
A solution of dihydro-2-t-butyldimethylsilyloxy-1H-pyrrolizine-3,5(2H,6H)-dione (2.1 g) in acetic acid:water, 3:1 (18 ml) is stirred at 60° C. for six hours. The solution is cooled, concentrated, toluene added and the solution reconcentrated. The oil is triturated with anhydrous ethyl ether and filtered to yield 2-hydroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid. NMR (CDCl3) and 5.48 (m, 1H), 4.47 (m, 1H), 4.10 (b.s., 1H), 2.93-1.36 (m, 6H). IR 3310, 2860, 1770, 1710, 1655, 1410, 1372, 1307, 1275.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:14])[CH2:12]Br)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH:22]([C:25]1[CH:31]=[CH:30][C:28](N)=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C[N:33](C=O)C>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:14])[CH2:12][NH:33][C:27]2[CH:28]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[CH:26]=2)[CH:5]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(NC(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cccc(NC(=O)CNc2cccc(C(C)C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
3-(2-Bromoacetylamino)benzoic acid methyl ester (8.09 g, 29.7 mmol) prepare above was mixed with potassium carbonate (4.93 g, 35.7 mmol) and 4-isopropylaniline (4.41 g, 32.7 mmol) in DMF (100 mL), and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuum and the residue was suspended in dichloromethane. The solid was filtered off and the filtrate was concentrated to give crude product, which was chromatographed (silica gel, hexanes:ethyl acetate, 8:2) to give 3-[2-(3-isopropylphenylamino)acetylamino]benzoic acid methyl ester as a pale yellow oil (8.18 g, 84.5%). MS (ES+) m/z: 327.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)=[O:3].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.N1C=CC=CC=1>[N:20]1([C:2]([C:4]2[CH:19]=[CH:18][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)=[CH:6][CH:5]=2)=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
4-(4-Chlorocarbonylbenzyl)-nitrobenzene was dissolved in dichloromethane (40 mL) and a solution of pyrrolidine (64 mg, 1 eq) in pyridine (0.2 mL) was added. The mixture was stirred for 2 hours at room temperature, washed with dilute potassium hydroxide, and solvents evaporated to yield a yellow oil. The residue was chromatographed on silica gel, eluting with dichloromethane/methanol, to give 4-(4-pyrrolidin-1-ylcarbonylbenzyl)-nitrobenzene (299 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Cl>CC(N(C)C)=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:24][O:25]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCCCc2ccccc2O)cc(OC)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCC1CO1
Product: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Yield: 79.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), 1.9 g of 2-[4-(3,5-dimethoxyphenyl)butyl]phenol (prepared as described in Preparation 9), 0.75 g of potassium t-butoxide and 0.91 g of epichlorohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified to give 1.81 g (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: O[CH:2]([CH3:6])[CH2:3][CH:4]=[O:5].[CH2:7]([C:9]([CH2:11]C)=O)[CH3:8].[CH:13](O)(C)C.[OH-].[Na+]>C(O)(=O)C>[CH3:13][C:3]1[C:4](=[O:5])[CH:7]([CH3:8])[CH:9]([CH3:11])[CH2:6][CH:2]=1
Reactant: CCC(=O)CC
Reactant: CC(O)CC=O
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1=CCC(C)C(C)C1=O
Yield: 47.1 %

Procedure:
A mixture of 88 g of β-hydroxybutyraldehyde and 150 g of diethyl ketone is added dropwise in the course of one hour to a mixture of 250 g of diethyl ketone, 80 g of isopropanol and 5 g of sodium hydroxide powder which is boiling under reflux. The whole is boiled for another hour under reflux. Neutralization is effected with glacial acetic acid and the aqueous phase is separated. The organic layer is fractionated. 65 g of 2,5,6-trimethyl-2-cyclohexen-1-one having a boiling point of 74° to 76° C. at 12 mm Hg is obtained. The yield is 47% with reference to β-hydroxybutyraldehyde.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>>[CH2:21]([NH:24][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)[CH:22]=[CH2:23]
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: Cc1ccc(CN)o1
Reactant: C=CCN
Product: C=CCNc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=294.4 (M+H+), was prepared in accordance with the general method of example 3 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and allylamine.
Reaction SMILES: CN1C=CN=C1.Cl[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:22]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: Cn1ccnc1
Product: CCOP(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
The following starting materials were fed continuously at 80° C. into a reactor which was equipped with a three-stage inclined-blade stirrer and had been made inert with nitrogen: 1) mixture of 110.7 g of ethanol and 205.8 g of 1-methylimidazole and 2) chlorodiphenylphosphine (99.4% strength). Stream 1) was added at 330 ml/h and stream 2) was added at 380 ml/h. Both streams were introduced below the surface of the liquid. The reactor was equipped with an overflow from which reaction mixture could flow out continuously. The reactor volume up to the overflow was 710 ml. The reaction temperature was maintained at 80° C. To bring the system to equilibrium, the output obtained over the first 4 hours was discarded. The output was subsequently collected over a period of 1 hour and a mass balance was carried out. The output consisted of two liquid phases. Over a period of one hour, 497.2 g of upper phase and 280.8 g of lower phase were collected. The upper phase comprised 96.8% of EODPP. The upper phase was subsequently distilled under reduced pressure via a column filled with Raschig rings, giving 438.2 g of 99.74% strength EODPP. Together with the EODPP in the first fraction, the total yield was 96.7%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([CH3:23])=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([CH3:23])=[CH:18][C:17]=1[S:24]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:13])[F:14])[N:11]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: Nc1cccc(COCC(F)(F)F)n1
Product: Cc1cc(S(=O)(=O)Nc2cccc(COCC(F)(F)F)n2)c(Cl)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-5-methyl-benzenesulfonyl chloride (0.11 g) as a light yellow gum (0.095 g). MS (ESI−): 427.1 ([M−H]−).
Reaction SMILES: CN(C)C=O.[C:6]([OH:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)([Cl:19])=O.Cl>>[C:6]([Cl:19])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)Cl

Procedure:
100.5 g (1.38 mol) of N,N-dimethylformamide were added to 2.75 mol of pelargonic acid in a stirred apparatus. The reaction solution was brought to a temperature of from 20 to 30° C. with stirring, and a total of 2.78 mol of gaseous phosgene and simultaneously 1.92 mol of gaseous hydrogen chloride were introduced under atmospheric pressure. When the addition of phosgene and hydrogen chloride was complete, the two phases were separated from one another. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of 1%. The carbonyl chloride phase comprised 98.9% by weight of pelargonoyl chloride and 0.04% by weight of pelargonic anhydride. The color number was 18 APHA.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.CO.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: C=CCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
2 G. of 1-acetamido-2-nitro-4-(prop-2-en-1-ylthio)-benzene is treated with 20 ml. methanol and 10 ml. 5N aqueous sodium hydroxide at 20°-25° C for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization from benzene yields 1-amino-2-nitro-4-(prop-2-en-1-ylthio)benzene. This latter compound in 200 ml. acetone is treated with 4 g. methoxy carbonyl isothiocyanate at room temperatue for several days (i.e., until no starting material is present). The mixture is concentrated and the residue triturated with methanol to yield 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(prop-2-en-1-ylthio)benzene.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].Br[CH2:10][CH2:11][CH2:12][Cl:13]>ClC1C=CC=CC=1>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][CH2:11][CH2:12][Cl:13])[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCNCC1
Reactant: ClCCCBr
Solvent: Clc1ccccc1
Product: O=CN1CCN(CCCCl)CC1
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 1-formylpiperazine (5.7 g, 50 mmol),1-bromo-3-chloropropane (7.2 ml, 11.8 g, 75 mmol) and chlorobenzene (30 ml) was stirred at 100°-105° C. for 3 hours. After cooling the separated 1-formylpiperazine hydrochloride (4.58 g, yield: 94.4%) was filtered off and the filtrate concentrated. The residue was chromatographed on a silica gel column eluting with a 8:2 mixture of ethyl acetate and methanol to afford 2.46 g of the oily title compound, yield: 51.6%.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[CH:54]=[C:53]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[C:52]2[C:47](=[CH:48][C:49]([C:61]([F:64])([F:63])[F:62])=[CH:50][CH:51]=2)[N:46]=1>CN(C=O)C>[CH2:9]([CH:3]([CH2:1][CH3:2])/[CH:4]=[CH:5]/[C:6]([N:58]1[CH2:59][CH2:60][N:55]([C:53]2[C:52]3[C:47](=[CH:48][C:49]([C:61]([F:64])([F:62])[F:63])=[CH:50][CH:51]=3)[N:46]=[C:45]([CH3:44])[CH:54]=2)[CH2:56][CH2:57]1)=[O:8])[CH3:10]
Reactant: Cc1cc(N2CCNCC2)c2ccc(C(F)(F)F)cc2n1
Reactant: CCC(/C=C/C(=O)O)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(/C=C/C(=O)N1CCN(c2cc(C)nc3cc(C(F)(F)F)ccc23)CC1)CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 320 %

Procedure:
(E)-4-Ethyl-hex-2-enoic acid (21.3 mg, 0.15 mmol) was dissolved in DMF (350 μl), diisopropylethylamine was added (26 μl, 0.15 mmol) followed by HATU (57 mg, 0.15 mmol dissolved in 0.25 ml DMF). The mixture was stirred at room temperature for 15 minutes, then 2-methyl-4-piperazin-1-yl-7-(trifluoromethyl)quinoline (44 mg, 0.15 mmol, dissolved in 1 ml DMF) was added and stirring was continued overnight. The mixture was evaporated under reduced pressure, the residue was dissolved in dichloromethane, the solution was washed with 5% sodium bicarbonate solution and water, evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 20.3 mg (0.48 mmol, 32.3%) of a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[C:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][C:23]=3[C:14]=2[CH:13]=1
Reactant: BrCCCN1CCCC1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCCN2CCCC2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(3-bromopropyl)pyrrolidine, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1.[H-].[Na+].I[CH3:36]>>[NH2:1][C:2]1[C:7]([N:8]([CH3:36])[C:9](=[O:14])[O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:15])[N:5]=[C:4]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:3]=1
Reactant: CI
Reactant: CC(C)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 6 with 75 mg (0.17 mmol) of isopropyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 3, 10.31 mg (0.26 mmol) of sodium hydride and 24.4 mg (0.17 mmol) of iodomethane. The residue is purified by preparative RP-HPLC.
Reaction SMILES: C([Mg:4][Br:5])(C)C.Cl[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].BrC1C(F)=C(F)C(F)=C(F)C=1F>C(OCC)C>[C:7]1([Mg:4][Br:5])[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17]
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Reactant: CC(C)[Mg]Br
Agent: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 50 °C
Reaction time: 7.5 h

Procedure:
To a diethyl ether solution of isopropyl magnesium bromide, chloropentafluorobenzene was added at 0 to 40° C. under nitrogen with stirring in a period of thirty minutes, such that the isopropyl magnesium bromide was in 1.03 to 1.05 molar excess of the chloropentafluorobenzene. The mixture was stirred at 47 to 53° C.; after 5 to 10 hours, bromopentafluorobenzene was added to react with the excess isopropyl magnesium bromide, and the mixture was stirred at 25° C. for 1 hour. Any excess bromo-pentafluorobenzene was back-titrated in situ with isopropyl magnesium bromide to form more C6F5MgBr. The yield of C6F5MgBr was 96.1%, and 3.9% C6F5Cl remained, as determined by 19F NMR, using C6H5CF3 as a reference; no trace of iPrMgBr was seen with 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].NC1C=CC=CC=1C(N)=O.[CH3:21][O:22][CH2:23][CH2:24]O>[Ni]>[CH3:21][O:22][CH2:23][CH2:24][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1cccc(N)c1
Reactant: COCCO
Agent: [Ni]
Agent: NC(=O)c1ccccc1N
Product: COCCNc1cccc(C(N)=O)c1

Procedure:
10 g of 3-aminobenzamide and 30 g of rainy nickel were mixed with 150 ml of 2-methoxy ethanol and refluxed for 15 hours. (Molar ratio of aminobenzamide:solvent=1:26.) Celite was added to the reaction mixture and the debris removed by filtration. The filtrate was then evaporated under reduced pressure and the product, 3-(2-methoxyethylamino)benzamide crystallized on cooling, mp 89°-91° C.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:61]=[CH:62][C:63]([NH2:66])=[N:64][CH:65]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[F:59][C:60]1[CH:61]=[CH:62][C:63]([NH:66][C:21]([C@@H:20]2[CH2:19][CH2:18][N:17]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[N:16]2[C:14](=[O:15])[C@@H:13]([CH2:12][N:3]([CH:1]=[O:2])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:35][CH2:36][CH3:37])=[O:22])=[N:64][CH:65]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1 g, 1.95 mmol) in THF (15 mL) under N2 was added 2,4,6-trichlorobenzoyl chloride (0.572 g, 2.34 mmol) and DIPEA (1.68 mL, 9.75 mmol). The mixture was stirred at rt for 2 h. THF was removed under vacuum and toluene (15 mL) was added. To this mixture was added 5-fluoro-2-pyridinamine (0.262 g, 2.34 mmol) and DMAP (47.5 mg, 0.39 mmol). After being stirred at rt overnight, the mixture was diluted with EtOAc (50 mL) and washed with citric acid and brine. The organic solution was dried and concentrated. The residue was purified by flash column chromatography eluting with EA/PE (1:5) to provide the title compound (0.23 g, 19%) as colorless oil.
Reaction SMILES: [CH2:1]([S:10][C:11]#[N:12])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([OH:23])(=[O:22])=[O:21])[CH:15]=1>[Cl-].[Zn+2].[Cl-].O>[C:4]1([C:2]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([OH:23])(=[O:21])=[O:22])[CH:15]=3)[S:10][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CSCC(=O)c1ccccc1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=S(=O)(O)c1cccc(Nc2nc(-c3ccccc3)cs2)c1

Procedure:
132 parts of phenacyl thiocyanate, 38 parts of zinc chloride and 129 parts of 1-aminobenzene-3-sulfonic acid are together stirred with 750 parts of water for 20 hours at the boil. After the mixture has cooled, the product is filtered off and dried.