Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CB(O)O
Reactant: Clc1ccn2c(CC3CC3)nnc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)ccn2c(CC3CC3)nnc12
Temperature: 100 °C

Procedure:
To a mixture of intermediate D70 (1 g, 3 mmol) in toluene (25 ml) under a nitrogen atmosphere were added methylboronic acid (0.897 g, 15 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine; X-Phos (0.286 g, 0.6 mmol), palladium(II) acetate (0.067 g, 0.3 mmol) and K2CO3 (1.243 g, 9 mmol). The reaction mixture was heated at 100° C. for two days. After cooling, the mixture was diluted with EtOAc and washed with water. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/EtOAc from 100/0 to 0/100 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D98 (0.365 g, 55%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.[F-].[Cs+]>O1CCOCC1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=3)[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(Br)ccc21)OCC
Reactant: COc1cccc(B(O)O)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOP(=O)(C=C1NCCN(C)c2cc(-c3cccc(OC)c3)ccc21)OCC
Temperature: 80 °C
Yield: 67.7 %

Procedure:
To 300 mg (0.77 mmol) of (8-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester (prepared as described in Example 41) in 1 ml of dioxane was added 123 mg (0.81 mmol) of 3-methoxyphenylboronic acid, 7.8 mg (0.028 mmol) of tricyclohexylphosphine, 10.5 mg 0.012 mmol) of tris-(dibenzylideneacetone)-palladium (0) and 141 mg of caesium fluoride. The mixture was heated at 80° C. for 6 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the product was purified by column chromatography (20 g IST pre-packed column) eluting with acetone—petroleum ether (40-60° C.) (1:2) to give 217 mg of [8-(3-methoxyphenyl)-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl]phosphonic acid diethyl ester as a yellow gum; MS: m/e 417 (M+).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[C:27]([CH3:28])=[CH:26][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:29])[CH:7]=1)\[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36](Br)[CH2:37][CH3:38]>C(#N)C.O>[CH3:29][C:8]1[CH:7]=[C:6](/[C:3](=[N:2]/[O:1][CH2:36][CH2:37][CH3:38])/[CH2:4][CH3:5])[C:27]([CH3:28])=[CH:26][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCBr
Reactant: CC/C(=N\O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCCO/N=C(\CC)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 0.12 g (0.3 mmol) of (E)-methyl 2-(2-((4-((E)-1-(hydroxyimino)propyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 4 and 0.2 g (0.61 mmol) of cesium carbonate in 10 mL of acetonitrile (CH3CN) was added propyl bromide (0.05 mL, 0.55 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum and the concentrate was purified by silica gel chromatography to afford 0.1 g of (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)propyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate as a white oil (yield: 77%).
Reaction SMILES: O[C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C:8](=[O:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1.O.O=P(Cl)(Cl)[Cl:27]>CN(C)C=O>[Cl:27][C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C:8](=[O:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1
Reactant: CC1(C)CC(=O)c2c(nc(O)c3c2C2(CCOCC2)OC3=O)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)c2c(nc(Cl)c3c2C2(CCOCC2)OC3=O)C1

Procedure:
6.2 g 4-Hydroxy-7,7-dimethyl-2′,3′,5′,6′,7,8-hexahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3,9(6H)-dione are suspended in 25 ml phosphoroxychloride, 1 drop of N,N-dimethylformamide is added and the mixture is heated for 18 hours to 65° C. Under vigorous stirring the mixture is added dropwise to 300 ml water while keeping the temperature below 35° C. After completion of the addition the mixture is stirred for 1 hour, the product is isolated by filtration, washed with water and dried in vacuo.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:27])[C:14]([NH:16][CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].O>C1COCC1>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[NH:16][C:14](=[O:15])[N:13]([CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=1)[CH3:27])[CH2:19]2
Reactant: COC(=O)c1ccc(OCCN(C)C(=O)NC2C3CC4CC(C3)CC2C4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C(=O)O)cc1)C(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 8 h

Procedure:
A solution of 4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid methyl ester 562 mg (1.45 mmol), NaOH 1N 3 ml in THF 5 ml was stirred at RT overnight. Then NaOH 1N 4 ml was added and the reaction mixture stirred overnight. Water was added and the mixture acidified until pH=2.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)(F)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCC(F)(F)CC1
Reaction time: 24 h

Procedure:
A solution of EXAMPLE 239A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then concentrated from toluene, and left on high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to provide the title compound as its trifluoroacetic acid salt.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:30])[CH3:29].Cl>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:30][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCN
Agent: Cl
Solvent: CC#N
Product: CCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 5 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.47 g, 1.09 mmol), ethanamine (1 ml, 70% in water) and ACN (7 ml). Yield: 0.278 g, 83%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 267° C. MS m/z (rel. intensity, 70 eV) 305 (M+, 4), 63 (3), 59 (4), 58 (bp), 56 (5). [α]=−62° (MeOH).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[CH:51][C:52]([F:56])=[C:53]([CH:55]=2)[NH2:54])[CH:38]=[CH:37][N:36]=1.[F:57][C:58]1[CH:59]=[C:60]([S:64](Cl)(=[O:66])=[O:65])[CH:61]=[CH:62][CH:63]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[CH:51][C:52]([F:56])=[C:53]([NH:54][S:64]([C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=3)(=[O:66])=[O:65])[CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.5 mmol) and 3-fluorobenzenesulfonyl chloride (8.72 g, 44.8 mmol) the title compound of Step A was obtained (9.3 g, 53.4%). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.52-7.60 (m, 1H), 7.41-7.50 (m, 2H), 7.20-7.37 (m, 1H), 7.04-7.12 (m, 1H), 6.83-7.00 (m, 2H), 3.30-3.40 (m, 1H), 1.46 (d, J=6.8 Hz, 6H). MS (ES+): 507 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 10.99 (s, 1H), 8.95-8.94 (m, 1H), 8.36-8.33 (m, 1H), 8.02-7.99 (m, 1H), 7.80-7.69 (m, 3H), 7.48-7.42 (m, 1H).
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].O>C(OCC)C>[Br:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC(Cc1ccccc1)c1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: BrC(Cc1ccccc1)c1ccccc1
Temperature: -10 °C
Yield: 84 %

Procedure:
To a solution of 12.0 (60.5 mmol) of 1,2-diphenylethanol in 50 mL of dry diethyl ether, 11.0 g (3.80 mL, 40.0 mmol) of PBr3 was added with vigorous stirring at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 350 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and evaporated to dryness. This procedure gave 13.2 g (84%) of the title product.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14]C(C)(C)C)=[O:13])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]([CH3:19])([CH3:20])[C:12]([OH:14])=[O:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1cccc(OC(C)(C)C(=O)O)c1
Reaction time: 3 h

Procedure:
tert-Butyl 2-(3-allyloxycarbonylphenoxy)-2-methylpropionate (11.59 g, 36.19 mmol) was dissolved in dichloromethane (20 mL). Subsequently, trifluoroacetic acid (40 mL) was added at room temperature, and the mixture was stirred for three hours. The reaction mixture was concentrated under reduced pressure, and toluene was added to the concentrate. The resultant mixture was concentrated again under reduced pressure. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby a yellow oil was obtained (8.30 g, 31.41 mmol, 86.7%).
Reaction SMILES: C1(C(C2C=CC=CC=2)C2CCNCC2)C=CC=CC=1.[N+](C1C=CC(CCl)=CC=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][N:47]2[CH2:52][CH2:51][CH:50]([CH:53]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:49][CH2:48]2)=[CH:42][CH:41]=1)([O-])=O.[H][H]>C(O)C.O.O1CCCC1.[Pd]>[C:60]1([CH:53]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:50]2[CH2:49][CH2:48][N:47]([CH2:46][C:43]3[CH:42]=[CH:41][C:40]([NH2:37])=[CH:45][CH:44]=3)[CH2:52][CH2:51]2)[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
The basic primary amine of this invention can be prepared by heating 4-(diphenylmethyl)piperidine with 4-nitrobenzyl chloride in the presence of sodium carbonate, using ethanol and water as solvents, and contacting the resultant 1-[(4-nitrophenyl)methyl]-4-(diphenylmethyl)piperidine in tetrahydrofuran solution at 25° with hydrogen under approximately 0.1 atm of pressure, using 5% palladium-on-charcoal as catalyst. From 4-{[4-(diphenylmethyl)-1-piperidinyl]methyl}benzenamine thus or otherwise produced, on heating in acetic acid solution with an alkanoic acid anhydride, a corresponding basic N-alkanoyl amine of this invention can be prepared. And by heating a dichloromethane solution of 4-(diphenylmethyl)piperidine and 4-[(alkylamino)/(dialkylamino)]benzoic acid in the presence of N,N1 -methanetetraylbiscyclohexanamine, then heating the resultant amide with lithium tetrahydroaluminate(1-) in tetrahydrofuran, a corresponding basic N-alkyl or N,N-dialkyl amine of this invention can be prepared.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]4[N:17]([N:21]=[C:22]([CH:24]=[CH:25][C:26]#[N:27])[CH:23]=4)[CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.[Pd]>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]4[N:17]([N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:27])[CH:23]=4)[CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: N#CC=Cc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: [Pd]
Solvent: CO
Product: N#CCCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 6 h

Procedure:
Pd/C (50 mg) is added to a solution of 2-(2-cyano-vinyl)-pyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)-amide in MeOH. The mixture is stirred under hydrogen balloon for 6 h. The mixture is filtered through celite and the celite and solvent are removed to give the title compound. LC-MS m/z (M+H+): 363.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1.O>[CH:16]1([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1nc(Cl)nc(NC2CCCCC2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2,4,6-Trichloro-1,3,5-triazine (92.2 g) was dissolved in 300 mL of dioxane at room temperature. 53 g of Na2CO3 was dissolved in 300 mL of distilled water and was slowly added into the above solution. Cyclohexylamine (49.95 g) in a dropping funnel was slowly added into the above solution while stirring at 0-5° C. for 2 hr. The stirring was continued for another 3 hr at 0° C., 1 hr at room temperature, and the resultant white precipitate was then filtered and washed with water. The white precipitate was dissolved in methylenechloride (MC) and washed with water and MC was evaporated. Finally, 6-cyclohexylamino-2,4-dichloro-1,3,5-triazine having a substituted cyclohexyl was obtained after drying and solvent removal. The yield was more than 90%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:2].[CH2:18]=[O:19]>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:18][OH:19])[N:7]=1)[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Solvent: CCO
Product: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12

Procedure:
A mixture of ethyl-4-oxo-3-H-phthalazin-1-ylacetate (23.42 g), ethanol (200 ml) and aqueous formaldehyde (37% concentration, 100 ml) was refluxed for 40 hours. This solution was concentrated to 100 ml and was then poured onto ice water (750 ml). The precipitated solid was collected and air-dried (yield: 17.1 g; m.p. 113°-114° C.).
Reaction SMILES: [CH2:1]([N:9]([CH2:19][C:20]([O:22]C)=[O:21])[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[CH2:1]([N:9]([CH2:19][C:20]([OH:22])=[O:21])[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN(CC(=O)OC)C(=O)CCCCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCN(CC(=O)O)C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
Methyl 2-(N-octyloctanamido)acetate (44.7 mg, 0.136 mmol) was dissolved in 0.5 mL of methanol and then 100 μL of 20% aqueous sodium hydroxide solution was added. The reaction mixture was then stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was diluted with 3 mL of ethyl acetate and then neutralized by adding 200 μL of 10% aqueous hydrogen chloride solution. After removing water with anhydrous magnesium sulfate and filtering out the precipitate, the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 36.5 mg (0.116 mmol, 86%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8](C(O)=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].[OH-].[Na+].[Br:18]Br>CC(C)=O.O.CCCCCC.[N+]([O-])([O-])=O.[Ag+].COC(C12CCC(C(O[Ag])=O)(CC1)CC2)=O>[Br:18][C:8]12[CH2:11][CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:10][CH2:9]1)[CH2:6][CH2:7]2
Reactant: BrBr
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Agent: COC(=O)C12CCC(C(=O)O[Ag])(CC1)CC2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)C12CCC(Br)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 353.4 %

Procedure:
To a suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (11.0 g, 51.8 mmol) in acetone (80 mL) was added aqueous sodium hydroxide solution (1 M, 51.8 mL, 51.8 mmol) and a solution of silver nitrate (8.8 g, 51.9 mol) in water (10 mL). The precipitate formed was collected by filtration, washed with water, acetone and diethyl ether and dried in vacuo at 115° C. for 4 h. The obtained ((4-(methoxycarbonyl)-bicyclo[2.2.2]octane-1-carbonyl)oxy)silver (15.3 g, 47.9 mmol) was suspended in hexane (125 mL), followed by addition of bromine (7.7 g, 48.1 mmol) over 30 min at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for another 30 min. The reaction mixture was filtered to remove the solid, and the filter cake was washed with hexane (150 mL×4). The combined organic filtrates were washed with saturated aqueous sodium bicarbonate solution (150 mL×2) and brine (200 mL), then dried over magnesium sulfate. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford the title compound (4.2 g, 0.17 mol, 33% yield over two steps). 1H NMR (400 MHz, CDCl3): δ ppm 3.64 (s, 3H), 2.27-2.20 (m, 6H), 1.98-1.94 (m. 6H).
Reaction SMILES: C([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]([O:9]C(=O)C)[C@H:6]1[NH2:7])(=O)C.[C:25]1([S:39](Cl)(=[O:41])=[O:40])[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:26]=1>C(#N)C.N1C=CC=CC=1>[C:25]1([S:39]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:41])=[O:40])[CH:30]=[C:29]([S:31]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:33])=[O:32])[CH:28]=[C:27]([S:35]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:37])=[O:36])[CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)S(=O)(=O)c1cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c1

Procedure:
The novel intermediate benzene 1,3,5-trisulfonyl trisglucosamine compound is prepared by reacting tetra-O-acetyl glucosamine (II) with 1,3,5-benzenetrisulfonyl chloride in a weakly basic polar medium such as acetonitrile-pyridine for 24 hours. The solvent is concentrated and the tetraacetyl trisulfonyl derivative (III) is precipitated from ice water and extracted into methylene dichloride. The solvent is evaporated and the material is dissolved in cold methanol saturated with ammonia. Standing in the cold for 24 hours, followed by the addition of nitrogen gas to remove ammonia, produces a thick oil (IV) on evaporation. The oil is purified from water with activated charcoal, filtration and drying to give the intermediate glucopyranose.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH:38]([NH2:40])[CH3:39])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH:38]([CH3:39])[CH2:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CC(N)Cc1ccc(F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(F)cc1)N1CCC2(CCN(S(=O)(=O)c3ccccc3Cl)CC2)C1=O

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Fluoro-phenyl)-1-methyl-ethylamine. MS (ESI): 465.3 (MH+).