Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:38])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH:25]2[CH:29]([OH:30])[CH2:28][N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26]2)[N:19]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:38])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH:25]2[C:29](=[O:30])[CH2:28][N:27]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26]2)[N:19]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CN(Cc3ccccc3)CC2O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CN(Cc3ccccc3)CC2=O)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (0.02 mol) in 30 mL of anhydrous CH2Cl2 was added dropwise oxalyl chloride (0.015 mol). The mixture was stirred at −78° C. for 10 min. After this time a solution of [6-(1-benzyl-4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester I-3 (0.01 mol) in 10 mL of anhydrous CH2Cl2 was added dropwise at a rate to keep the reaction temperature below −60° C. Upon complete addition, the mixture was allowed to stir at −78° C. for 2 h. Then anhydrous triethylamine (0.03 mol) was added dropwise to the mixture. After complete addition, the reaction mixture was allowed to warm to room temperature. The resulting solution was partitioned between 1 M NaOH (40 ml) and the product was extracted with CH2Cl2 (30 ml×2). All organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to yield crude product, which was purified using column chromatography (silica gel, CH2Cl2:EtOAc, 4:1) (87%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([CH2:19]O)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:21][CH3:22])[CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[ClH:25].[CH2:1]([NH:8][C:9]1[C:18]([CH2:19][Cl:25])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:21][CH3:22])[CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nc(NCc3ccccc3)c(CO)cc2c1
Solvent: ClCCl
Product: COc1ccc2nc(NCc3ccccc3)c(CCl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of (2-(benzylamino)-6-methoxyquinolin-3-yl)methanol SLA 41006 (0.101 g, 0.343 mmol) in dry CH2Cl2 (50 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (0.50 mL, 6.86 mmol). The mixture was stirred for 1 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give N-benzyl-3-(chloromethyl)-6-methoxyquinolin-2-amine hydrochloride SLA 41008 (120 mg, 100% yield) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([CH3:43])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:44])=[CH:17][C:18]=4[CH3:43])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 93 %

Procedure:
A solution of 0.071 g (0.115 mmole) of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-191) in 4 mL of dichloromethane was stirred with 2 mL of trifluoroacetic acid for 2 hours and concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0549 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-piperidin-4-yl-benzamide (I-192) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](Cl)(=[O:10])[CH3:9]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:8]([N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1c[nH]c(C)n1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)n1cc(C)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 9.6 g (0.10 M) of 2,4-dimethylimidazole in 50 ml of chloroform and 50 ml of toluene was stirred at room temperature and 3.6 ml (0.05 M) of acetyl chloride was added via syringe over 1 minute. The mixture was stirred at room temperature for 2 hours, then the mixture was filtered to remove insoluble solids, and the filtrate concentrated leaving 6.9 g (100%) of 1-acetyl-2,4-dimethylimidazole as a white crystalline solid: nmr (CDCl3) (δ): 7.00 (s, 1H); 2.68 (s, 3H); 2.57 (s, 3H); 2.21 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH:2]([CH3:13])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C(=O)C(C)Br)ccc1O
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)ccc1O

Procedure:
12.15 g (0.05 mol) of 2-bromo-4'-hydroxy-3'-methylpropiophenone are dissolved in 25 ml of ethanol, 8.75 g (0.05 mol) of 4-benzylpiperidine diluted in 25 ml of ethanol, and then 5.4 g (0.05 mol) of sodium carbonate, are added and the mixture is heated under reflux for 1 and a half hours. The solvent is driven off and the residue is chromatographed on 100 g of silica using acetone as the eluant. This gives 18.4 g of a thick oil, which is used as such.
Reaction SMILES: [NH2:1][C:2]([C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]([NH:23][C@H:24]([C:30]([NH:32][C:33]4([C:36]#[N:37])[CH2:35][CH2:34]4)=[O:31])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[CH:20]([F:22])[F:21])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:3].[CH3:38][S:39]([OH:42])(=[O:41])=[O:40].C(OC)(C)(C)C>C1COCC1>[CH3:38][S:39]([O-:42])(=[O:41])=[O:40].[NH2:1][C:2]([C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]([NH2+:23][C@@H:24]([CH2:25][C:26]([F:29])([CH3:27])[CH3:28])[C:30]([NH:32][C:33]4([C:36]#[N:37])[CH2:35][CH2:34]4)=[O:31])[CH:20]([F:22])[F:21])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)cc2)cc1)C(F)F)C(=O)NC1(C#N)CC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(F)C[C@H]([NH2+][C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)cc2)cc1)C(F)F)C(=O)NC1(C#N)CC1
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of N2-((1S)-1-{4′-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2-difluoroethyl)-N1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide (112 mg, 0.219 mmol) in THF (8 mL) was added 0.21 mL of methanesulfonic acid (1M solution in dichloromethane) followed by methyl t-butyl ether (2 mL). Seed crystals were added and the mixture was allowed to stand until a crystal bed had formed. The solvent was removed and the solid was suspended in methyl t-buty ether and heated to reflux overnight. Cooled to room temperature, filtered and dried under vacuum to give the title compound. m.p. 126 C
Reaction SMILES: C([Zn:3]CC)C.[CH:6]([OH:9])([CH3:8])[CH3:7]>CCCCCCC>[CH3:7][CH:6]([CH3:8])[O-:9].[Zn+2:3].[CH3:7][CH:6]([CH3:8])[O-:9]
Reactant: CC[Zn]CC
Reactant: CC(C)O
Solvent: CCCCCCC
Product: CC(C)[O-]
Product: [Zn+2]

Procedure:
A 0.1 M solution of diethylzinc in heptane (40 ml, Aldrich) was transferred into a 500-ml three-neck round bottom flask equipped with a thermometer, addition funnel, magnetic stirring and a Liebig condenser attached to argon-vacuum line. Anhydrous isopraponol (6 ml, Aldrich) was slowly added under vigorous stirring. Additional 50 ml of anhydrous isopropanol were added and the mixture was refluxed for 1 hour. Volatiles were removed under reduced pressure affording white crystalline zinc isopropoxide, which was dried under vacuum at 80° C. for an hour. Dry cyclohexane (250 ml) was added into the flask, and the solid quickly dissolved. The mixture was heated to 55-60° C., and 17.0 g of acetoxypentamethyldisiloxane (82 mmol) in 50 ml of dry cyclohexane was added dropwise during 1 hour under vigorous stirring. The mixture was heated to 55-60° C. for additional 2 hours and was allowed to cool to room temperature. Volatiles were removed under reduced pressure. A solid waxy residue was dried under vacuum at 50° C., then was transferred into a sublimation apparatus, and was sublimed at 110° C./0.02 torr to afford 9.7 g of white solid Zn(OSi(CH3)2OSi(CH3)3)2.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:7]2[CH:3]1[CH2:4][C:5](=[O:12])[CH:6]2[C:8](=O)[CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)[Cl:34]>C(Cl)(Cl)(Cl)Cl>[Cl:34][C:8](=[C:6]1[C:5](=[O:12])[CH2:4][C@H:3]2[C@@H:7]1[C:2]2([CH3:13])[CH3:1])[CH2:9][CH3:10]
Reactant: ClC(Cl)Cl
Reactant: CCC(=O)C1C(=O)CC2C1C2(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Cl)=C1C(=O)C[C@H]2[C@@H]1C2(C)C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(1S,5R)-6,6-dimethyl-2-propionyl-bicyclo[3.1.0]hexan-3-one (14.37 g, 80 mmol) in chloroform (145 mL) and CCl4 (53 mL), triphenylphosphine (41.8 g, 160 mmol) is added. The resulting solution is stirred at 60° C. for 75 min before a second portion of triphenylphosphine (4.2 g, 16 mmol) is added. Stirring is continued at 60° C. for 30 min. The solvent is evaporated and the residue is suspended in pentane. The pentane solution is decanted from the brown oily residue. The residue is once more treated with pentane. The combined pentane fractions are carefully evaporated to leave crude (1R,5S)-2-[1-chloro-propylidene]-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (11.0 g) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH2:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Li])[CH2:25][CH2:26][CH3:27].[Cl-:29].[Cl-].[Cl-].[Cl-].[Zr+4:33]>C(OCC)C>[Cl-:29].[Cl-:29].[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]([Zr+2:33][CH:24]3[C:17]4[C:27](=[CH:22][CH:23]=[CH:15][CH:16]=4)[CH:26]=[C:25]3[C:7]3[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1cc(C2=Cc3ccccc3C2)cc(C(C)(C)C)c1
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3ccccc3C2[Zr+2]C2C(c3cc(C(C)(C)C)cc(C(C)(C)C)c3)=Cc3ccccc32)cc(C(C)(C)C)c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
2-(3,5-Di-t-butylphenyl)indene (13.8 g, 0.045 mol) and anhydrous diethyl ether (250 mL) were placed in a 1 L three-necked flask under argon. n-Butyllithium (28 mL of a 1.6 M solution in hexanes, 0.045 mol) was added over a thirty minute period at 0° C. The solution was stirred for an additional two hours. Zirconium tetrachloride (5.1 g, 0.022 mol) was added incrementally over a one hour period. The mixture then was stirred overnight. The ethereal solution was chilled to −10° C. and the solids were collected. The solids were taken up in 300 mL of dichloromethane and the residual solids were removed by filtration through celite. The celite was washed with an additional 100 mL of dichloromethane and the solvents were evaporated to give 11.2 g of product (64% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[ClH:1].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNCc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A suspension of ethyl glycinate hydrochloride (944 mg) in DMF (6.0 mL) was stirred for 5 min. p-Iodobenzyl bromide (2.00 g) was added. The heterogeneous system was warmed to 50° C. and stirred for 5 min, during which time, most solids dissolved. K2CO3 (2.80 g, granular) was added steadily over 5 min. After 2 h, the reaction was cooled to 23° C. Conc. aq. HCl (3.3 mL) was added, followed by H2O (7.0 mL). The heterogeneous mix was stirred for 15 min and filtered (the cake was washed with CH3CN (4×5 mL)). The net filtrate was concentrated until no CH3CN remained. The crude product solution was filtered through a 0.45 micron Teflon filter and loaded directly onto a Teledyne Isco ‘gold’ 100 gram column and flashed (Eluent: 0.05% w/v aq. HCl/CH3CN 95:5→0:100), giving DK (688 mg, 29% yield) as an HCl salt. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.78 (s, 2H), 7.84 (d, J=7.8 Hz, 2H), 7.36 (d, J=7.8 Hz, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.15 (s, 2H), 3.95 (s, 2H), 1.25 (t, J=7.0 Hz, 3H). LCMS-ESI+: calc'd for C11H16INO2: 320.0 (M+H+). Found: 319.9 (M+H+).
Reaction SMILES: C(OC(=O)C)(=O)C.[P:8]([OH:11])([OH:10])[OH:9].O[CH2:13][NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(=O)C>[C:15]([NH:14][CH2:13][P:8]([OH:11])(=[O:10])[OH:9])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCO)c1ccccc1
Reactant: OP(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(NCP(=O)(O)O)c1ccccc1
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
561 g (5.5 mol) of acetic anhydride were cooled to 10° C. Then, a solution of 164 g (2.0 mol) of phosphorous acid and 300 ml of acetic acid were added dropwise in the course of one hour, with stirring and cooling. 302 g (2.0 mol) of N-hydroxymethylbenzamide were then added in portions in the course of 50 minutes at 10°-15° C., with cooling. Stirring was continued at 10° C. for 20 minutes. The reaction mixture was subsequently kept under reflux for 2.5 hours, followed by cooling. 61 g (3.39 mol) of water were then added dropwise at 25°-30° C., with cooling and stirring. After this, the mixture was refluxed again. After cooling, the mixture was stirred overnight and solids were then filtered off with suction. 320 g (approx. 75% of theory) of crude benzoylaminomethanephosphonic acid were obtained. Further crude acid could be obtained from the mother liquor.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=1)[CH:17]=O.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:17]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[CH:19]=1
Reactant: Nc1cc[nH]n1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=Cc1cc(Br)ccc1O
Product: CC1(C)CCC2=C(C1=O)C(c1cc(Br)ccc1O)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 5-bromo-2-hydroxybenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5].[N+:19]([C:22]1[C:23]([CH:35]=O)=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][CH:27]=1)([O-:21])=[O:20].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+]>[CH:13]1([CH:2]([NH:1][CH2:35][C:23]2[C:22]([N+:19]([O-:21])=[O:20])=[CH:27][N:26]=[C:25]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:24]=2)[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)CCNC(=O)CC(N)C1CCCCC1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture 3-amino-3-cyclohexyl-N-(3,3-dimethyl-butyl)-propionamide (0.57 g, 2.24 mmol), 5-nitro-2-phenoxy-pyridine-4-carbaldehyde (0.57 g, 2.35 mmol), and dichloroethane (100 mL) was stirred for 12 hrs. Sodium triacetoxyborohydride (1.09 g, 5.15 mmol) was added and the resulting mixture was stirred 4 hours at room temperature. Sodium hydroxide solution ([0.1N], 100 mL) was added, the organic layer was separated, treated with MgSO4, filtered and the solvent evaporated under reduced pressure to yield an oil. The oil was purified by column chromatography (10%-40% ethyl acetate/heptane) to yield a residue.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][C:10](=[O:17])[CH2:11][C:12](=O)[CH2:13][CH2:14][CH3:15])[CH3:8].O>C1C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:17])[CH:11]=[C:12]([Cl:2])[CH2:13][CH2:14][CH3:15])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCC(=O)CC(=O)OCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC(Cl)=CC(=O)OCC
Temperature: 20 °C

Procedure:
280 g of phosphorus pentachloride are added in portions over the course of 2 hours to a solution of 200 g of 3-oxo-hexanoic acid ethyl ester in 20 ml of absolute benzene whilst stirring at 20° C. 200 ml of water are then added dropwise with intense cooling so that the temperature never rises above 0° C. The mixture is stirred for a further 12 hours at 0° C. The organic phase is then separated off, washed with twice 100 ml of ice-cold 2 N sodium hydroxide solution and with twice 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Fractional distillation of the evaporation residue gives, in the fraction boiling at 98°-102° C (20 mm), crude 3-chloro-2-hexenoic acid ethyl ester, which is used direct for further conversion.
Reaction SMILES: OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Mg+2].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16]([OH:18])=[O:17].[CH3:23][C:24](O)([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16]([O:18][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:17]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(F)cc(F)c1
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
Concentrated H2SO4 (1.74 mL, 31.6 mmol) was added to a vigorously stirred suspension of MgSO4 (15.2 g, 126.4 mmol, 4 eq) in toluene (100 mL). The mixture was stirred for 15 minutes, after which 3,5-difluorobenzoic acid (5 g, 31.6 mmol) and t-BuOH (14.9 mL, 158 mmol, 5 eq) were added successively. The mixture was stoppered tightly and stirred at room temperature until the reaction was complete by TLC analysis. The reaction mixture was then quenched with saturated NaHCO3 solution and stirred until all MgSO4 had dissolved. The organic layer was washed with brine, dried over MgSO4 and concentrated to afford the crude product. The residue was purified by chromatography (silica, Hex) to give tert-butyl 3,5-difluorobenzoate (5.3 g, 78%) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:18])[CH2:10][CH2:9]3)[CH2:6]1)=[N+]=[N-].[H][H]>O1CCCC1.[C].[Pd]>[NH2:1][CH2:4][CH:5]1[O:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:18])[CH2:10][CH2:9]3)[CH2:6]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: NCC1Cc2c(ccc3c2CCC(=O)N3)O1
Yield: 81.3 %

Procedure:
The compound obtained in Example 161 (0.53 g, 2.17 mmol) dissolved in tetrahydrofuran (26 ml) was combined with 10% palladium-carbon (0.32 g), then stirred in the stream of hydrogen at ambient temperature for 1.5 hour. After completion of the reaction, palladium-carbon was filtered off from the reaction mixture. The palladium-carbon was washed with tetrahydrofuran and then methanol. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: ammonia/methanol=20:1). 0.385 g of the tile compound was obtained as colorless crystals (87.9%, mp.: 162°-163° C.).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[NH:9][C:8](=[O:10])[NH:7][C:6](=[O:11])[CH:5]=1>C(O)(=O)C>[Br:1][C:5]1[C:6](=[O:11])[NH:7][C:8](=[O:10])[NH:9][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)[nH]c(=O)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
Bromine (39.97 g, 0.25 mole) was added dropwise to a cooled mixture of 31.5 g (0.25 mole) of 6-methyl-2,4(1H,3H)pyrimidinedione in 200 ml of glacial acetic acid. The resulting mixture was stirred at ambient temperature for 16 hours and then filtered. The solid which was collected was washed with water and dried in vacuo overnight at 69° C. to give 39.9 g of the product as a white solid, mp 254° C. (dec.).
Reaction SMILES: [C:1](=[O:4])([O-])O.[K+].[CH3:6][OH:7].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>>[Cl:10][C:9]1[N:11]=[C:12]([O:7][CH3:6])[N:14]=[C:15]([O:4][CH3:1])[N:8]=1
Reactant: CO
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Agent: [K+]
Product: COc1nc(Cl)nc(OC)n1
Temperature: 10 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 105.1 g (1.05 mol) of potassium hydrogencarbonate and 160.2 g (5.0 mol, water content: 530 ppm) of methanol were placed. With stirring at a temperature of not higher than 10° C., 92.2 g (0.5 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 50° C. for 4 hours. The weight of the reaction solution from which a salt formed had been removed was 230 g, and the water content was 79,800 ppm. After *cooling, methanol was distilled off. To the residue, 400 ml of water was added, and the objective product was extracted with 500 ml of ethyl acetate. The organic layer was washed with 400 ml of water and then vacuum concentrated to obtain 72.7 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 82.8%. From the gas chromatography analysis, the purity proved to be 94.9% (% by area).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:9]([CH2:31][CH3:32])[C:10]1[N:30]=[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][C:22]=3[C:27](O)=[O:28])=[O:20])=[CH:17][N:12]2[N:11]=1)[CH3:8]>>[CH2:31]([N:9]([CH2:7][CH3:8])[C:10]1[N:30]=[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][C:22]=3[C:27]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:28])=[O:20])=[CH:17][N:12]2[N:11]=1)[CH3:32]
Reactant: C1COCCN1
Reactant: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Product: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)cn2n1

Procedure:
Using morpholine and 5-(2-diethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (65 mg, 94%). MS: m/z=357 (M+H+).