Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2].O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:15])[C:11]([CH2:13][O:14][C:17]3[CH:49]=[CH:48][C:20]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]4=[O:47])=[CH:19][CH:18]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc2nc(CO)n(C)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 88.9 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.00 g of 5-ethoxy-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 98), 2.25 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.2 ml of tributylphosphine, 1.22 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.81 g of the title compound, melting at 88-100° C. (softening).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].[CH:19]([N:22]=[C:23]=[O:24])([CH3:21])[CH3:20]>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (2.24 g, 8.91 mmol) in CH2Cl2 (30 mL) was treated with isopropyl isocyanate (1.1 mL, 11 mmol). The reaction mixture was diluted with water, the CH2Cl2 was removed under reduced pressure, and the aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to the title compound as a white solid (2.6 g, 87%). MS (ES+) m/z 337 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][CH2:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cc(Br)cc2N1
Yield: 97.3 %

Procedure:
2-Amino-4-bromo-6-flourophenol (95MF2084) (0.078 g, 0.38 mmol), 2-chloroacetyl chloride (0.048 g, 0.42 mmol) and K2CO3 (0.11 g, 0.79 mmol) were mixed according to GP1 to give the title compound as a crude (95MF44) (0.091 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([OH:33])=O)[C:6]=2[CH:34]=1.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:37]([CH3:38])[CH3:36])=[O:33])[C:6]=2[CH:34]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CC(=O)O)c3cc(Cl)ccc32)cn1
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CC(=O)N(C)C)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To a solution of 7-chloro-5-carboxymethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.35 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolydinyl)phosphinic chloride (0.24 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. To the mixture are added with stirring dimethylamine hydrochloride (0.078 g) and triethylamine (0.31 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-dimethylaminocarbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.29 g) as white powder.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(OCC)C(NCCCCOc1ccccc1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(NCCCCOc1ccccc1)P(=O)(O)O
Yield: 53.3 %

Procedure:
A mixture of tetraethyl 4-phenoxybutylaminomethylenebisphosphonate (1.37 g) and concentrated hydrochloric acid (20 ml) was heated for two hours under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate was treated with water to give 4-phenoxybutylaminomethylenebisphosphonic acid (0.549 g, 53%), m.p. 206° C. to 208° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:41]=[CH:40][C:27]2[N:28]=[C:29]([N:31]([CH3:39])[CH2:32][CH2:33][N:34]([CH3:38])[C:35](=[O:37])[CH3:36])[S:30][C:26]=2[CH:25]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[C:35]([N:34]([CH3:38])[CH2:33][CH2:32][N:31]([CH3:39])[C:29]1[S:30][C:26]2[CH:25]=[C:24]([NH:23][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[CH:19][CH:18]=3)=[O:22])[CH:41]=[CH:40][C:27]=2[N:28]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)N(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 4 drops of DMF to a stirring suspension of 4′-fluoro-biphenyl-4-carboxylic acid (0.243 g, 1.13 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution to a mixture of rac-N-{2-[(6-amino-benzothiazol-2-yl)-methyl-amino]-ethyl}-N-methyl-acetamide (0.146 g, 0.524 mmol) and pyridine (0.06 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5-10% ethyl acetate/n-hexane to remove impurities, then flushing off product with 2N NH3/MeOH). Triturate the residue with CH2Cl2 to yield the desired product as a white solid (0.110 g, 44%). mass spectrum (m/e): 477.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=O)[C:8]=2[CH:19]=1)([O-:3])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=[S:21])[C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccccc2Sc2ccc([N+](=O)[O-])cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(=S)Nc1ccccc1S2
Reaction time: 8 h
Yield: 154.2 %

Procedure:
2-Nitro-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.27 g) was dissolved in toluene (20 ml). Phosphorus pentasulphide (0.22 g) was added to the solution and the whole was stirred under reflux for 4 hours, then cooled and left overnight. Addition of water (40 ml) and separation of the phases gave, after evaporation of the dried organic layer, a yellow solid which was purified by column chromatography on silica gel and recrystallisation from ethanol to give the product as yellow needles (0.22 g, m/s. M+ =288).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:13]1([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:20][C:13]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(Br)CCCCCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\OC1(C)CCCCCC1)C(C)=O
Reaction time: 5 h
Yield: 65.2 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (795 mg, 5 mmol) and 1-bromo-1-methylcycloheptane (1.lg, 5.76 mmol) in dry 1,4-dioxan (5 ml) under an atmosphere of argon in the dark were treated portionwise with silver trifluoromethanesulphonate (1.48 g, 5.76 mmol), with stirring, over 5 h. The mixture was stirred for a further 18 h in the dark and then worked up using a similar procedure to that described in Example 7a to give the title compound as an oil (878 mg; 65%); νmax (CH2Cl2) 3430, 3350, 1740, 1685, 1595, 1370, 1320, 1230, 1070, and 1,000cm-1 ; δH (250 MHz, CDCl3) 1.33 (3H, t, J 7.1Hz), 1.33 (3H, s), 1.4-1.8 (1OH, m), 1.99 (2H, dd, J ca 13.5 and 7.5 Hz), 2.40 (3H, s), and 4.35 (2H, q, J 7.1 Hz); [Found: M30 -OEt 224.1273. C12H18NO3 requires M-OEt 224.1287. Ammonia CI mass spectrum MH+ (270)].
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1.C[OH:27]>C1(C)C=CC=CC=1>[CH:11]1([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:27])=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: CO
Reactant: N#Cc1ccc(NC2CC=CCC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(NC2CC=CCC2)cc1
Temperature: 0 °C

Procedure:
Di-isobutylaluminium hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 4-(cyclohex-3-enylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with acqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dicloromethane/hexane giving colorless needles.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:30])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.IC1C=CC(NC(C2C=CC(N3CCC(C(O)=O)CC3)=NC=2)=O)=CC=1C>>[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[CH:13][CH:14]=2)=[O:30])[CH:25]=[CH:24][CH:23]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)ccc1I
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)cc2)c1

Procedure:
1-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid was prepared by the hydrolysis of 1-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid ethyl ester with LiOH monohydrate in a manner similar to the one described in the synthesis of 5′-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid above. HRMS m/z calcd for C23H28N2O3 [M+H]+: 381.2173. Found: 381.2173.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].[CH2:12]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14]>>[CH2:12]([N:15]([CH2:16][CH2:17][CH3:18])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=1)[CH2:13][CH3:14]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CCCNCCC
Product: CCCN(CCC)C(=O)c1cccc(C=O)c1

Procedure:
To 2 g (13.3 mmole) of 3-formyl benzoic acid was coupled with di-n-propylamine via Method I to give 2.5 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:29]([O-])(=O)C.[Na+].C(O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:29][NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of the compound of Example 46 (135 mg, 0.34 mmol), sodium acetate (28 mg, 0.34 mmol) and acetic acid (41 mg, 0.68 mmol) in methanol (3.4 mL), formaldehyde (37% in water, 0.033 mL, 0.41 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) were added. The mixture was stirred for 1 hour, concentrated, diluted with ethyl acetate and washed with water and brine, dred and concentrated. The residue was subjected to preparative HPLC on a 30×500 mm ODS S10 column using 56% methanol, 44% water and 0.1% trifluoroacetic acid to provide 23 mg of the title compound (16%) as a white solid, m.p. 125-128° C., as well as 30 mg of the title compound of Example 50 (20%) as a light yellow solid, m.p. 127-129° C.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([S:16]([NH:19][C@H:20]([C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][C:37]([O:39]CC)=[O:38])[CH2:32][CH2:31]2)=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([S:16]([NH:19][C@H:20]([C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:32][CH2:31]2)=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC1CCN(C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c2cccc(C(C)(C)c3ccccc3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N2CCC(CC(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1-(Nα -(3-(α,α-dimethylbenzyl)benzenesulphonyl)-(S)-arginyl)-4-(ethoxycarbonylmethyl)piperidine (500 mg) in absolute ethanol (2.5 ml) is added aqueous 1M NaOH (1.7 ml) and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then chromatographed on Amberlite resin CG120(H+) (25 ml). The resin column is eluted fast with aqueous 50% ethanol until neutral pH, then with ethanol/H2O/NH3 (sp.gr. 0.88) (5:4:1). The fractions containing the product are evaporated to give a residue which is co-evaporated (3 times) with ethanol, triturated with ether, collected by filtration, washed with ether and dried in vacuo. Thus is obtained 1-(Nα -(3-(α,α-dimethylbenzyl)benzenesulphonyl)-(S)-arginyl)piperidine-4-acetic acid, m.p. 188°-191° C., Rf (BuOH/HOAc/H2O 3:1:1) 0.58. 13C NMR spectrum is consistent with the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[O:13].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C.O>[CH2:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:21][CH2:22]2)=[CH:18][CH:19]=1)=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C3CC3)cc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C3CC3)cc2)c1

Procedure:
A mixture of 490 mg (1.68 mmol) of the aniline prepared in step D, 256 μl benzaldehyde and 150 μl AcOH in 5 ml MeOH is treated with 200 mg 95% sodium cyanoborohydride. Temperature is kept around rt by a cooling bath. After 5 hours the reaction mixture is distributed between water and ethyl acetate. The crude orange oil obtained after concentration i.V. is purified by chromatography (hexane/ethyl acetate) to yield a yellow solid. m.p. 116-118° C.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.Cl.[CH3:53][N:54]1[CH2:57][CH:56]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:61]2[CH2:62][CH2:63][N:58]([CH:56]3[CH2:57][N:54]([CH3:53])[CH2:55]3)[CH2:59][CH2:60]2)=[O:7])[CH:24]=1
Reactant: CN1CC(N2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)C1
Reaction time: 25 h
Yield: 33.6 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (106 mg) and triethylamine (0.167 ml) at room temperature, followed by stirring for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (20.2 mg, 33%).
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]([OH:16])=O)[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]([CH3:60])[CH2:58][OH:59]>CN(C=O)C.O>[OH:59][CH2:58][CH:57]([NH:56][C:14]([C:4]1[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:2][N:7]=[N:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[CH3:60]
Reactant: CC(N)CO
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CO)NC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
To a solution of methyl 3,5-diphenylpyrridazine-4-carboxylic acid (compound 6) (250 mg, 0.90 mmol) in DMF (3 mL), DIPEA (0.47 mL, 2.71 mmol), HATU (516 mg, 1.35 mmol) were sequentially added and stirred at rt. After 15 min. 2-amino-1-propanol (203 mg, 2.71 mmol) was added and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). Combined organic extract was washed with water (2×10 mL), brine (1×10 mL) and dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the crude product N-(1-hydroxy propan-2-yl)-3,5-diphenylpyridazine-4-carboxamide (160 mg) as an off white solid.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:39])[C:8]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[CH:38]=[CH:37][C:22]([C:23]([NH:25][C@H:26]([C:33]([O:35]C)=[O:34])[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:24])=[CH:21][CH:20]=2)=[C:9]([NH:11]C(=O)C)[N:10]=1)(=O)C.C(O)C.[OH-].[Na+].N1C=CC=CC=1>O.C(O)CCC>[NH2:4][C:5]1[NH:6][C:7](=[O:39])[C:8]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]([C:33]([OH:35])=[O:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:37][CH:38]=2)=[C:9]([NH2:11])[N:10]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(NC(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCCCO
Product: Nc1nc(N)c(CCCNc2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)c(=O)[nH]1

Procedure:
A stirred solution of 1.60 g (2.89 mmol) of dimethyl N-[4-[3-(2,4-bis(acetamido)-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino]benzoyl]-L-glutamate, 50 ml of ethanol and 100 ml of 1N sodium hydroxide was heated at 50°-60° for 20 hours. The cooled reaction was spin evaporated in vacuo to 50 ml, cooled, and neutralized to pH 5-6 with concentrated hydrochloric acid. The resultant white precipitate was collected, washed with water, diethylether and dried; yield, 0.86 g (66%) mp (sinter 170°) 198°-202° (eff). Recrystallization from methanol gave the analytical sample; yield, 0.33 g (39%), mp (forms hard foam 180°) 200° (eff); TLC (pyridine:BuOH:H2O/1:1:1); NMR (DMSO-D6) δ8.07 (d, 1H, ArCONH), 7.65 (d, 2H, ArH), 6.54 (d, 2H, ArH), 6.22 (br s, 1H, CH2NH), 5.94 (s, 2H, NH2), 5.75 (s, 2H, NH2), 4.34 (m, 1H, CHCO2H), 3.03 (m, 2H, CH2NHAr), 2.30 (m, 4H, pyrimidine-CH2 and CH2CO2H), 2.03 (m, 2H, CHCH2), 1.58 (m, 2H, CH2CH2CH2).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].C1COCC1.Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Cl:24][C:22]1[CH:23]=[C:18]([NH:6][C:5]2[C:4]([F:3])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Nc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Nc1cc(Cl)nn2ccnc12
Temperature: 50 °C

Procedure:
To 60% NaH (22.5 mg, 0.563 mmol) in DMF (400 μl) was added 2,6-difluoroaniline (24 mg, 0.186 mmol). After stirring at RT for 5 minutes THF (1000 μl) was added followed by 8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.186 mmol, prepared as described in Example 1, step (1b). The reaction was heated at 50° C. for 3 hours. The reaction was quenched with a few drops of water and methanol. The solution was then concentrated in vacuo to give crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine.