Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[OH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[C:26][CH2:27][OH:28])[N:23]=2)[N:18]=[CH:17][C:16]=1[C:29](OCC)=[O:30]>C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:29]([C:16]2[CH:17]=[N:18][C:19]3[C:24]([C:15]=2[OH:14])=[N:23][C:22]([C:25]#[C:26][CH2:27][OH:28])=[CH:21][CH:20]=3)=[O:30])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(C#CCO)nc2c1O
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)nc2c1O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Trimethylaluminum (2 M in toluene, 42 μL) is added dropwise to a room temperature solution of 4-chlorobenzylamine (17 μL) in CH2Cl2 (1 mL) under nitrogen. The solution is stirred for 5 minutes before the addition in one portion of ethyl 4-hydroxy-6-(3-hydroxy-1-propynyl)[1,5]naphthyridine-3-carboxylate (Preparation 2, 19 mg). The reaction is stirred at room temperature for 3.5 h. The reaction mixture is partitioned with dil. aq. HCl (2 mL) and extracted with CH2Cl2 (2×2 mL). After drying over MgSO4, the extracts are concentrated under vacuum. The crude residue is flash chromatographed (silica, 10% methanol/CH2Cl2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: CO
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: [Na]
Product: COC(=O)c1cc(OC)ccn1

Procedure:
A mixture of methyl 4-chloropyridine-2-carboxylate (3.7 g), sodium metal (0.5 g) and methanol (100 ml) was stirred and heated to reflux for 8 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give methyl 4-methoxypyridine-2-carboxylate (3 g).
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH2:9][OH:10])[CH2:6][CH2:7][CH3:8])[CH2:2][CH3:3].CN1CCOCC1.[S:18](Cl)(Cl)=[O:19].O>ClCCl>[CH2:1]([N:4]1[CH:5]([CH2:6][CH2:7][CH3:8])[CH2:9][O:10][S@:18]1=[O:19])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCN[C@@H](CO)CCC
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC1CO[S@@](=O)N1CCC
Temperature: 25 °C
Yield: 81 %

Procedure:
(R)—N-Propylnorvalinol (11.53 g) was dissolved in dichloromethane (160 mL), and N-methylmorpholine (21.8 mL) was added thereto under stirring at room temperature. A solution of thionyl chloride (6.9 mL) in dichloromethane (48 mL) was added dropwise to the resulting solution over 120 minutes under stirring at 2° C. The resulting suspension was stirred at room temperature for 4 hours. Water (104 mL) was added to the suspension under stirring at 3° C. The mixture was separated and the organic layer was washed with an aqueous 1 mol/L hydrochloric acid solution (104 mL) and subsequently with a saturated aqueous sodium hydrogen carbonate solution (104 mL), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dried under reduced pressure at room temperature for 19 hours to give (R)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide as a red oil (12.36 g, 81% yield, cis:trans=about 45:55 determined from the integration ratio in 1H-NMR).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([Cl:35])=[CH:37][CH:38]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) and 4-chlorobenzoyl chloride (0.15 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (31 mg) which was characterized by its mass spectrum: MS m/z (%): 497 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:14])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[O:19][CH:20]=[CH:21][N:22]=1>>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:14])[CH2:17][C:18]1[O:19][CH:20]=[CH:21][N:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Reactant: ClCc1ncco1
Product: CC(C)(C)OC(=O)N(Cc1ncco1)c1cnccc1I

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (example 85, intermediate d) and 2-chloromethyl-oxazole (CAS RN 185246-17-7). Light yellow oil (93%). MS (ESI): m/z=402.031 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH3:16])(=[O:12])=[O:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH3:16])(=[O:12])=[O:11]
Reactant: CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCNS(=O)(=O)c1ccccc1N
Reaction time: 12 h
Yield: 99.3 %

Procedure:
To a solution of 2-nitro-N-propylbenzenesulfonamide (8.64 g, 0.035 mol) in methanol (100 mL) was added palladium on carbon (10%, 3.5 g). The mixture was stirred under an atmosphere of hydrogen for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated. The solid residue was washed with ether to afford 2-amino-N-propylbenzenesulfonamide (7.45 g, yield 98.3%), which was dissolved in ether, and bubbled in hydrochloride (gas) to afford the product 2-amino-N-propylbenzenesulfonamide hydrochloride (8.61 g, yield 98.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (br s, 3H), 7.50-7.62 (m, 2H), 7.26-7.30 (dt, 1H, J=1.6 Hz, 7.6 Hz), 6.88-6.90 (d, 1H, J=8.0 Hz), 6.67-6.71 (m, 1H), 2.61-2.65 (t, 2H, J=7.2 Hz), 1.28-1.37 (sext, 2H, J=7.2 Hz), 0.72-0.76 (t, 3H, J=7.6 Hz).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>[N+](C)([O-])=O>[N+:7]([C:17]1[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[C:13]([CH:16]=1)[CH:14]=[O:15])([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: O=Cc1ccccc1OC(F)(F)F
Agent: F[B-](F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=Cc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Reaction time: 2 h
Yield: 60.8 %

Procedure:
Nitronium tetrafluoroborate (14.0 g, 105 mmol) was added to a solution of 2-trifluoromethoxy-benzaldehyde (10.0 g, 52.6 mmol) in nitromethane (30 mL) at room temperature. The mixture was stirred for 2 h and was then quenched with ice water and extracted with ether (100 mL). The organic layer was separated, washed with water, dried over MgSO4 and chromatographed with 5% EtOAc/hexanes to afford 7.52 g of 5-nitro-2-trifluoromethoxy-benzaldehyde (60.8%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>COCCOC.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.O>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 0.175 g (0.5 mmol) of methyl N-[(4-bromophenyl)sulfonyl]-L-valinate, 0.25 g (1.5 mmol) of 4-nitrophenylboronic acid, 0.087 g of tetrakis(triphenylphosphine)palladium and 8 mL of saturated sodium bicarbonate in 8 mL of ethylene glycol dimethyl ether were refluxed for 2 h, then cooled to room temperature. To the reaction was added 50 mL of ethyl acetate and 40 mL of water. The water layer was extracted with ethyl acetate. The combined ethyl acetate layers was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexane:ethyl acetate (2:1) to provide 0.159 g of methyl N-[(4′-nitro-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate as a yellow solid. Yield 81%. m.p. 144-146° C.; MS: 391.0(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH3:14].C([Li])CCC.[O:20]1[C:22]([CH3:39])([CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]1.O>O1CCCC1>[CH3:12][O:11][C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[C:4]([CH3:14])[C:5]=1[CH2:13][CH2:39][C:22]([CH3:21])([OH:20])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC1(C)CO1
Reactant: COc1c(C)c(C)c(OC)c(C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
1.8 g (9 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene were dissolved in 100 ml of tetrahydrofuran, treated with 1 g (9 mmol) of potassium tert.butylate and subsquently 6 ml (9.5 mmol) of n-butyllithium (1.6 molar) were added dropwise at room temperature. Thereafter, the mixture was stirred at room temperature for 30 minutes, treated dropwise with 2.7 g (9 mmol) of (2RS,6RS,10RS) -1,2-epoxy-2,6,10,14-tetramethylpentadecane and stirred at room temperature for 16 hours. Thereupon, HYFLO and 200 ml of water were added, the mixture was then filtered and washed with water. The residue was stirred up with diethyl ether and sodium sulphate, filtered, washed with diethyl ether and concentrated. There were obtained 3.8 g of (3RS,7RS,11RS)-1-(2,5-dimethoxy-3,4,6-trimethyl phenyl)-3,7,11,15-tetramethyl-3-hexadecanol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:5]3[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]=3)[CH2:20][CH2:19]2)=[O:23])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3)CC2)n1
Reaction time: 20 h
Yield: 67.3 %

Procedure:
A mixture of 1-[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (80.0 mg, 0.255 mmol), 4-chlorobenzylamine (32.0 mg, 0.255 mmol), EDCI (49.0 mg, 0.255 mmol), HOBt (35.0 mg, 0.255 mmol) and N-methylmorpholine (26.0 mg, 0.255 mmol) in CH2Cl2 (5 mL) was stirred for 20 h (reaction progress monitored by LCMS). The solvent was removed under vacuum, and the residue was purified by preparative HPLC to yield 75 mg of the title compound as a white solid. MS (ES+): m/e 437.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncccc1Cl
Yield: 66.4 %

Procedure:
3-Chloropyridine-1-oxide (2.59g, 20 mmol), trimethylsilyl cyanide (5.95g, 60 mmol), and triethylamine (4.05g, 40 mmol) were combined in 40 mL of acetonitrile and reacted as described in example 763A. The solvent was removed in vacuo and the residue partitioned between CH2Cl2 and 3M potassium carbonate. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude product by silica gel chomatography using 5% ether/CH2Cl2 as the eluent gave compound 775B (1.84g, 67%) as a white crystalline solid. HPLC: 100% at 1.64 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 139.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl-].[NH4+]>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (3.13 g, 16.2 mmol) in dry tetrahydro-furan (40 mL), under nitrogen, was added magnesium turnings (0.39 g, 16.2 mmol). The mixture was refluxed for 1 h, cooled to ambient temperature and a solution of 1-N-boc-3-pyrrolidinone (2.0 g, 10.8 mmol) in dry tetrahydrofuran (10 mL) was added drop wise. The resulting mixture was refluxed 1 h, cooled to ambient temperature, aqueous saturated ammonium chloride solution (40 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated to give the title compound (3.38 g). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 243 (42), 198 (49), 168 (31), 127 (28), 57 (bp).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([F:17])([F:16])[F:15])=[C:4]([C:18](OCC)=[O:19])[S:3]1.B(F)(F)F.CCOCC.[H-].C([Al+]CC(C)C)C(C)C.[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:5]([C:14]([F:17])([F:16])[F:15])=[C:4]([CH2:18][OH:19])[S:3][C:2]1=[O:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1sc(=O)n(Cc2ccccc2)c1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=c1sc(CO)c(C(F)(F)F)n1Cc1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
3.13 g of the product of Step A, 30 ml of toluene and 1.3 ml of boron trifluoride etherate were stirred for 30 minutes at -65° to -70° C. and 48 ml of 1.2M solution of diisobutyl aluminium hydride in toluene were added over 2 hours. The mixture was poured into an iced molar solution of sodium and potassium tartrate and after stirring for one hour and decanting, extraction was carried out with ethyl acetate. The extracts were washed, dried and brought to dryness and the residue was chromatographed on silica. Elution with a hexaneisopropyl ether mixture (1-1) yielded 2.16 g of the expected product with a Rf=0.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: NN
Reactant: Cc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
13.0 g of 3-chloro-5,6,7,8-tetrahydro-6-(o-toluoyl)pyrido[4,3-c]pyridazine and 100 cc of hydrazine hydrate are reacted as described in Example 4. Reaction time 2 hours. The bis[3-hydrazino-5,6,7,8-tetrahydro-6-(o-toluoyl)pyrido[4,3-c]pyridazine]trisfumarate has a M.P. of 98°-100° (decomp., from 95% ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C@@:8]2([F:40])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([C:21]([O:23][CH2:24][C:25]([O:27]CC(OCC3C=CC=CC=3)=O)=[O:26])=[O:22])[C:9]2=[O:39])[CH:7]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C@@:8]2([F:40])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)[N:10]([C:21]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])[C:9]2=[O:39])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(=O)OCC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc21
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(=O)O)c2cc(C(F)(F)F)ccc21
Yield: 54 %

Procedure:
A solution of (S)-2-(3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carbonyloxy)acetic acid, benzyloxycarbonylmethyl ester (XII2) (95 mg, 0.17 mmol) in methanol (50 mL) was hydrogenated with Pd—C(10%) as catalyst at room temperature. Prep. HPLC purification afforded the title compound (42.4 mg) with 98% HPLC purity (yield 53.3%). 1H NMR (CDCl3, 500 MHz) δ 8.34 (s, 1H), 7.79 (d, 1H), 7.47 (d, 1H), 7.36 (dd, 1H), 7.31 (dd, 1H), 6.76 (dd, 1H), 5.08 (d, 1H), 4.96 (d, 1H), 3.57 (s, 3H); LC-MS, 462.88 (MH+, 99%); MS (m/e) 462 (M+1).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7](=[O:14])[C:8]([CH2:10][C:11](O)=[O:12])=[CH2:9]>C(OCC)C>[C:7]([CH:8]1[CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[C:11](=[O:12])[CH2:10]1)([O:6][CH3:5])=[O:14]
Reactant: C=C(CC(=O)O)C(=O)OC
Reactant: CC(C)N
Solvent: CCOCC
Product: COC(=O)C1CC(=O)N(C(C)C)C1
Reaction time: 24 h

Procedure:
In the course of 30 minutes, 59.1 g (1 mol) of isopropyl amine were added dropwise to 158 g (1 mol) of itaconic acid methyl ester in 120 ml of diethyl ether. When the slightly exothermic reaction had finished, the reaction mixture was allowed to stand for 24 hours at room temperature. Then the solvent was removed in vacuo and the residue was subjected to fractionated vacuum distillation. boiling point: 95-98° C/0.05 mm Hg; nD20 : 1.4680
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.N[C@H](C(N1CCC[C@H]1C(N[C@H](C([NH:86][C@H:87]([C:104]([O:106][CH2:107][C:108]1[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=1)=[O:105])[CH2:88][CH2:89][CH2:90]CNC(OCC1C=CC=CC=1Cl)=O)=O)C)=O)=O)CCCNC(=N)NS(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20]([N:86]1[CH2:90][CH2:89][CH2:88][C@H:87]1[C:104]([O:106][CH2:107][C:108]1[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=1)=[O:105])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
At 0° C. the solution of 18 mg (0.075 mmol) of HCl Pro-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 33 mg (0.077 mmol) Boc-Arg(Tos)-OH, 10 mg (0.074 mmol) of 1-hydroxybenzotriazole and 16 mg (0.077 mmol) of dicyclohexylcarbodiimide in 10 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 5 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 30 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (10 ml×3), saturated NaCl in water (10 ml×3) and KHSO4 in water (5%, 10 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, filtered. The filtrate was evaporated to provide 37 mg (80%) of the title compound as a colorless powder. Mp 60–62° C., FAB-MS (m/e) 617[M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH2:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][NH:36][CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A3) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.
Reaction SMILES: [OH-].[Li+].CC1(C)[O:9][C:8](=[O:10])[C:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:6](=[O:31])[O:5]1.O1CCCC1.O.Cl>O>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)([C:6]([OH:31])=[O:5])[C:8]([OH:10])=[O:9])=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CC1(C)OC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
2.185 g (52.07 mmol) of lithium hydroxide are added to a suspension of 10.79 g (26.04 mmol) of 2,2-dimethyl-5,5-bis(4-nitrobenzyl)-1,3-dioxane-4,6-dione and 110 ml mixture of tetrahydrofurane:water 9:1. The mixture is subsequently allowed to react for 21.5 hours at 25° C., added to 500 ml water and acidified to pH=1 with 20 ml hydrochloric acid 3N. The mixture is partitioned between water and ethyl acetate; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue 9.54 g (98%) of 2,2-bis(4-nitrobenzyl)malonic acid as white powder is used without further purification.