Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][NH:15][CH3:16].Cl>O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CNC
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
30.0 g (148 mmol) of 5-chloro-2-nitrobenzoic acid was dissolved by stirring in 78 mL (744 mmol) of 50% dimethylamine aqueous solution under cooling in the ice bath. After the solution was put into a pressure-resistant container and sealed, the solution was stirred by heating in the oil bath for 23 hours at 60° C. The reaction solution was sufficiently cooled down and the inner pressure thereof was released. After confirming completion of the reaction by HPLC analysis, the reaction solution was put into another container (using 50 mL of water), 49.6 mL of concentrated hydrochloric acid, and then 200 mL of water were added thereto. Yellow crystals were precipitated by addition of hydrochloric acid. The crystallizing solution was matured at 10° C. overnight, separated by filtration and dried under reduced pressure to obtain 30.95 g of 5-dimethylamino-2-nitrobenzoic acid. (yield 99%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCC(C)CC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Product: CC1CCN(c2ccc(C(=O)O)cc2F)CC1

Procedure:
Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate was treated with lithium hydroxide by method P. This resulted in the product with the molecular weight of 237.28 (C13H16FNO2); MS (ESI): 238 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=1.NN>C(Cl)Cl>[CH2:1]([N:4]([C:14]([NH:13][C:11]1[S:12][C:8]([O:7][CH3:6])=[N:9][N:10]=1)=[O:15])[NH2:5])[CH2:2][CH3:3]
Reactant: COc1nnc(N=C=O)s1
Reactant: CCCNN
Agent: NN
Solvent: ClCCl
Product: CCCN(N)C(=O)Nc1nnc(OC)s1
Temperature: 25 °C

Procedure:
A solution of propylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-propyl-4-(5-methoxy-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: O.[C@@H]1([N:11]2[C:21]3[N:20]=[C:18]([NH2:19])[NH:17][C:15](=[O:16])[C:14]=3[N:13]=[CH:12]2)O[C@H](CO)[C@@H](O)[C@H]1O.[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)#[N:23].Cl>CS(C)=O>[NH2:19][C:18]1[NH:17][C:15](=[O:16])[C:14]2[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:22]#[N:23])[CH:12]=[N:11][C:21]=2[N:20]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: N#Cc1ccccc1CBr
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1Cn1cnc2nc(N)[nH]c(=O)c21

Procedure:
Prepared by reacting 20.00 g of guanosine-hydrate with 22.54 g of 2-cyano-benzylbromide in dimethylsulphoxide at 60° C. and subsequent treatment with 57 ml of conc. hydrochloric acid.
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[C:5]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]2[CH2:13][CH2:14][N:15]([CH2:1][CH2:2][OH:3])[CH2:16][CH2:17]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethylene bromohydrin (0.37 ml) was added dropwise with stirring to a mixture of 4-diphenylmethylpiperidine (1 g), potassium carbonate powder (1.1 g) and N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure, followed by addition of water and extraction with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was purified by silica gel chromatography [eluent: CH2Cl2 --MeOH (25:1, v/v)] to give 4-diphenylmethyl-1-piperidineethanol as an oil. Yield 1.08 g (91.9%).
Reaction SMILES: [C:1]([C:5]1[CH:34]=[CH:33][C:8]([C:9]([N:11]2[CH2:16][CH:15]3[CH:13]([CH:14]3[CH2:17][N:18]([C:26]3[CH:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=3)[C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>N1CCCCC1>[C:1]([C:5]1[CH:34]=[CH:33][C:8]([C:9]([N:11]2[CH2:16][CH:15]3[CH:13]([CH:14]3[CH2:17][N:18]([C:26]3[CH:31]=[CH:30][C:29]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:28][CH:27]=3)[C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)N2CC3C(C2)C3CN(C(=O)c2cccs2)c2ccc(Cl)nc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc(C(=O)N2CC3C(C2)C3CN(C(=O)c2cccs2)c2ccc(N3CCCCC3)nc2)cc1
Temperature: 150 °C
Yield: 73 %

Procedure:
A stirring solution of the Thiophene-2-carboxylic acid [3-(4-tert-butyl-benzoyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]-(6-chloro-pyridin-3-yl)-amide prepared above (50 mg, 0.10 mmol) in 1 mL of anhydrous piperidine was heated to 150° C. for 18 hours. The mixture was cooled to room temperature, quenched with water, and extracted with Et2O. The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to yield the desired compound (40 mg, 73%).
Reaction SMILES: C(OC[N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10](=[O:17])[N:9]([CH3:18])[C:8]=2[N:7]=[CH:6]1)C.Cl>C(O)C>[CH2:15]([N:11]1[C:12](=[O:14])[C:13]2[NH:5][CH:6]=[N:7][C:8]=2[N:9]([CH3:18])[C:10]1=[O:17])[CH3:16]
Reactant: CCOCn1cnc2c1c(=O)n(CC)c(=O)n2C
Agent: Cl
Solvent: CCO
Product: CCn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
28.7 g (0.11 mol) of 7-ethoxymethyl-1-ethyl-3-methylxanthine were stirred at 60° C. for 60 hours in a solution of 200 ml of 5N hydrochloric acid and 200 ml of ethanol. The reaction mixture was concentrated to dryness and the residue which remained was crystallized in ethyl acetate/diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][CH2:49][S:50]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][N:61]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[CH3:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=2)=[CH:17][C:13]=1[C:14]([NH:66][C:63]1[CH:64]=[N:65][C:60]([NH:59][C:56]2[CH:57]=[CH:58][C:53]([S:50]([CH2:49][CH2:48][CH2:47][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)(=[O:51])=[O:52])=[CH:54][CH:55]=2)=[N:61][CH:62]=1)=[O:16]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)O
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 13.5 %

Procedure:
To a solution of intermediate 3 (Example 5) (170 mg, 0.5 mmol) in anhydrous CH2Cl2 (8 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (100 mg, 0.6 mmol) and 4-methylmorpholine (210 mg, 2 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 2 (Example 3) (100 mg, 0.3 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a white solid (27 mg, 15%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[N:3]=1.CC(C)([O-])C.[Na+].[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([F:24])=[CH:19][N:18]=1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Br:9][C:4]1[N:3]=[C:2]([NH:16][C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([F:24])=[CH:19][N:18]=2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: Cc1cc(N)ncc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: Cc1cc(Br)nc(Nc2cc(C)c(F)cn2)c1
Temperature: 88 °C

Procedure:
Into a flask were added 2,6 dibromo-4-methyl pyridine (10.0 g, 40.0 mmol), sodium tert-butoxide (4.4 g, 46.0 mmol), 2-amino-4-methyl-5-fluoro pyridine (5.8 g, 45.8 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.3 g, 1.9 mmol) followed by nitrogen sparged 1,4-dioxane (100 mL). The slurry was evacuated and refilled with nitrogen three times and then heated to 88° C. for 5 hours. After cooling to 25° C., ethyl acetate (100 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with 10% aqueous sodium chloride solution (25 mL) and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-50% ethyl acetate/hexanes) to afford N-(6-bromo-4-methylpyridine-2-yl)-5-fluoro-4-methylpyridine-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.07 (d, J=0.8 Hz, 1H), 7.61 (s, 1H), 7.32 (d, J=5.6 Hz, 1H), 6.87 (s, 1H), 2.20 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>ClCCl>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
1-(4-Nitro-phenyl)-piperazine (2 g, 9.65 mmol) is dissolved in dichloromethane (50 mL) and (BOC)2O is added (2.10 g, 9.65 mmol). The mixture is stirred at room temperature overnight. Solvent removal affords a yellow solid (2.96 g, 100% yield, ES+(m/z) 308 [M+H]).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:6]1([S:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of imidazole (27.2 g, 0.4 mol), and benzenesulphonyl chloride (35.3 g, 0.2 mol) in dry tetrahydrofuran (200 ml) was stirred at ambient temperature for 1 h, when the resulting precipitate was removed by filtration. The filtrate was evaporated under reduced pressure and the resulting solid was recrystallised from benzene/petroleum ether (b.p. 40°-60°), to afford 1-(benzenesulphonyl)imidazole, m.p. 82°-83°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:14]1[CH:13]=[C:12]([S:9]([NH:8][CH2:7][C:5]2[S:6][C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=3)=[CH:3][CH:4]=2)(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(NCc1ccc(Br)s1)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1

Procedure:
In analogy to example 1, step 3, N-(5-bromo-thiophen-2-ylmethyl)-3-chloro-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 440.3 ([M−H]−)
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C3C=CC(C(N4CCN(C)CC4)=O)=CC=3)C=2)C=1.Br[C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]([CH3:51])[CH3:50])[N:46]=[C:45]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)[CH:44]=2)[CH:40]=[N:41][CH:42]=1.[CH:58]([N:61]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=2)[CH2:63][CH2:62]1)([CH3:60])[CH3:59]>>[CH:58]([N:61]1[CH2:62][CH2:63][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([C:37]3[CH:38]=[C:39]([C:43]4[CH:48]=[C:47]([N:49]([CH3:51])[CH3:50])[N:46]=[C:45]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=5)[CH:44]=4)[CH:40]=[N:41][CH:42]=3)=[CH:70][CH:69]=2)[CH2:65][CH2:66]1)([CH3:60])[CH3:59]
Reactant: CN(C)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: CNc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)c2)cc(-c2ccccn2)n1
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(-c5ccccn5)nc(N(C)C)c4)c3)cc2)CC1

Procedure:
This compound is prepared analogously to [4-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (Example 2.1) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1 step1) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-dimethyl-amine and by replacing (4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 4-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[C:11]([C:18]([O:20]CC)=[O:19])[CH:10]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[C:11]([C:18]([OH:20])=[O:19])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(I)cc(-c2ccc(F)cc2F)cc1C(=O)O

Procedure:
This compound was obtained by saponification of the ester of the previous example (Example 16) (ethyl 2′,4′-difluoro-4-methoxy-5-iodo-[1,1′]biphenyl-3-carboxylate). The ester (200 mg, 0.48 mmol) was dissolved in 20 ml of ethanol and a 2.5 N solution of NaOH for 2 hr. After cooling, the mixture was acidified with hydrochloric acid and extracted with dichloromethane. After the work-up, a crude was obtained that was recrystalized from a chloroform/hexane mixture.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][CH:26]([NH2:34])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CC1[N:44](C(C2C=CC(Cl)=CC=2)=O)[C:43]2C=CC(OC)=CC=2C=1CC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][CH:26]([NH2:34])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[NH2:44][CH2:43][CH2:25][C:26]1[N:34]=[CH:30][NH:29][CH:27]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SCC(N)C(=O)NCC(=O)O)[C@@H](O)CCCC(=O)O
Product: NCCc1c[nH]cn1
Reaction time: 1 h

Procedure:
Antagonism for LTD4 was determined in isolated male guinea-pig (300-400 g) trachea prepared as spiral strip. Tracheal preparations were suspended under 1 g tension in 10 ml organ baths containing 5 μM of indomethacin and they were incubated for 1 hr prior to use. Contractile responses to LTD4 (2×10-8 g/ml) were obtained after the maximal response to histamine (10- 4 M). Test compounds dissolved in 100% dimethyl sulfoxide were added to the organ baths (final concentration of 10-6 g/ml or 10-7 g/ml) 30 min prior to LTD4 addition, and then contractile responses to LTD4 were compared with those of control which was obtained from a paired trachea in the absence of test compounds. LTD4 -induced contractions were expressed as a percentage of the maximal response to histamine. The antagonism was determined as follows:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[N:21]1([CH2:20][CH2:19][O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCCN1CCCC1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: OCCOc1cccnc1OCCN1CCCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 1-(2-hydroxyethyl)pyrrolidine (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 71 mg (0.28 mmol, 72%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH3:35])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH3:35])[CH2:25][NH:26][CH2:27]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CNC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirred solution of tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylazetidine-1-carboxylate (75 mg, 0.16 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature. Then the solution was stirred at room temperature for 2 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(3-methylazetidin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (40 mg, 52%) as a pale yellow solid. MS: (M+H)+=380; 1H NMR (300 MHz, DMSO): δ 13.04 (brs, 1H), 9.14 (s, 1H), 8.98 (brs, 2H), 8.56-8.51 (m, 2H), 8.38 (s, 1H), 7.72 (dd, 1H, J=9.6, 2.1 Hz), 7.24 (td, J=9.2, 1.8 Hz), 4.57 (d, 1H, J=10.8 Hz), 4.17 (s, 3H), 4.99 (d, 1H, J=10.8 Hz), 1.78 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:15]2[C:14](=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:13]([C:24]([N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27]2)=[O:25])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N3CCc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
According to the procedure of Yamada et al. (Note 2), a solution of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid (100 mg, 0.3 mmol) and 1,2,3,4-tetrahydro-isoquinoline (44 mg, 0.33 mmol) in 5 mL of THF was stirred at 0° C. under a nitrogen atmosphere. Diethyl cyanophosphonate (54 mg, 0.33 mmol) in 2 mL of THF was added followed by triethylamine (77 μL, 0.55 mmol). The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 15 h. The reaction was diluted with EtOAc and then washed with water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with NH4OH (10% solution in H2O) and then with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The resulting residue was triturated with ether to give 87 mg (66%) of the desired product. H1-NMR (CDCl3): δ 8.30 (s, 1H), 7.27 (broad m, 4H), 6.75 (m, 1H), 6.58 (m, 2H), 5.09 (m, 2H), 4.41 (m, 2H), 3.98 (m, 2H), 3.83 (s, 2H), 3.50 (s, 3H), 3.09 and 2.77 (m, 1H each), 1.52 (s, 9H), [Note: broadening of peaks observed due to Boc group, rotamers also observed.] MS: APCI (M+H) calc'd for C27H31N3O5+H 478.6; found 478.0.
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH:15](O)=[O:16]>>[CH3:14][C:8]1[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[C:5]=1[CH2:6][NH:7][C:2]([NH:1][CH:15]=[O:16])=[N:3]2
Reactant: O=CO
Reactant: CCCc1nc(C)c2n1N=C(N)NC2
Product: CCCc1nc(C)c2n1N=C(NC=O)NC2

Procedure:
2-Amino-3,4-dihydro-5-methyl-7-propylimidazo[ 5,1-f]-as-triazine (Example 1a) (2.2 g.) in formic acid (50 ml., 99°) was heated under reflux for 24 hours and evaporated under reduced pressure. The residue was stirred with 2N sodium carbonate and the solid was collected and dried and had m.p. 188.5°-190.5°. Its hydrogen maleate salt had m.p. 159°-161° (crystallised from a mixture of methanol and ether).