Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[N:27][N:26]=[C:25]1[C:39]12[CH2:46][CH2:45][C:42]([C:47]([NH:49][NH2:50])=[O:48])([CH2:43][CH2:44]1)[CH2:41][CH2:40]2>CN(C=O)C>[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:36])([F:38])[F:37])=[N:27][N:26]=[C:25]1[C:39]12[CH2:46][CH2:45][C:42]([C:47]([NH:49][NH:50][C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][C:7]([F:10])([F:9])[F:8])=[O:48])([CH2:41][CH2:40]1)[CH2:43][CH2:44]2
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)NN)(CC1)CC2
Reactant: CC(CC(F)(F)F)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(CC(F)(F)F)C(=O)NNC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Reaction time: 0.5 h

Procedure:
A solution of 2-methyl-4,4,4-trifluorobutyric acid (108 mg, 0.692 mmol) and 1,1′-carbonyldiimidazole (101 mg, 0.623 mmol) in DMF (1 ml) was stirred at room temperature under a nitrogen atmosphere. After 30 min, compound 13-A (100 mg, 0.254 mmol) was added and the solution stirred overnight. DMF was removed in vacuo and the solid was redissolved in CH3CN (4 ml). Product was purified by Gilson reverse phase chromatography eluting with a 10-90% CH3CN (0.1% TFA)/water (0.1% TFA) gradient. Solvent was removed in vacuo and the product free based from methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and the solvent removed to yield 13-B as a white solid. MS (ESI+)=532.18 (M+1).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([NH2:12])=[CH:6][CH:5]=1.[S:13](N)(N)(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][S:13](=[O:15])(=[O:14])[N:10]([CH3:11])[C:8]=2[CH:9]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1c2cc(Br)ccc2NS1(=O)=O

Procedure:
A mixture of 5-bromo-N1-methylbenzene-1,2-diamine dihydrochloride (800.0 mg, 3.00 mmol) and sulfamide (560 mg, 5.80 mmol) in pyridine (10 mL) was heated at reflux for 2 h. Pyridine was removed under reduced pressure and the residue obtained was dissolved in DCM (20 mL) and washed with 1N HCl (20 mL). The DCM layer was separated, dried over Na2SO4, filtered, and concentrated to obtain 6-bromo-1-methyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.98 (d, J=2.0 Hz, 1H), 7.93 (dd, J=8.8, 2.3 Hz, 1H), 7.46 (d, 1H), 3.41 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([C:29]2([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[N:19][N:20]=2)[N:17]=1>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)[C:13]([C:29]3([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: Cn1ncnc1CO
Reactant: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccc(F)cc3F)nnc2cc1C1(C)CCCCC1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 13 mg, 0.33 mmol) was added to a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210; 37 mg, 0.33 mmol) in anhydrous N,N-dimethylformamide (5 ml) at room temperature under nitrogen. This was stirred for 30 mins and 6-chloro-3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.275 mmol) in N,N-dimethylformamide (3 ml) was then added and the mixture stirred for a further 60 minutes. The reaction was quenched with water (20 ml) and stirred for an additional 60 minutes. The precipitated solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane (20 ml), filtered and evaporated. The residue was recrystallised from ethyl acetate/hexane to give the title compound (38 mg): m.p.=196° C.; 1H NMR (360 MHz, CDCl3) δ 1.32 (3H, s), 1.33-1.66 (6H, m), 1.72-1.81 (2H, m), 1.93-2.03 (2H, m), 3.87 (3H, s), 5.50 (2H, s), 7.00-7.14 (2H, m), 7.83-7.90 (1H, m), 7.91 (1H, s), 8.00 (1H, s); MS (ES+) m/e 440 [MH]+; Anal. Found: C, 59.74; H, 5.23; N, 22.10. C22H23F2N7O requires: C, 60.13; H, 5.27; N, 22.31%.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])[NH:6][CH:7]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])[NH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1ccccn1-c1ccc(-c2nc(CO)c[nH]2)c(F)c1
Product: O=c1ccccn1-c1ccc(-c2nc(CCl)c[nH]2)c(F)c1

Procedure:
Alternatively as shown in Scheme 4, 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as above, is treated with 4-hydroxymethylimidazole II-1 in the presence of 8-hydroxyquinoline, and K2CO3 in DMSO. The resulting mixture is degassed before being charged with CuI to give 4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-1. The compound 4-1 is treated with thionyl chloride to give 4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole which is then treated with NaN3 to result in 4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-2. The azide 4-2 is reduced with Ph3P to give 4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-3. The compound 4-3 is then treated with 5-chlorothiophene-2-carboxylic acid 1-5 to give the title compound 21.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[C:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]1([CH2:31][CH2:32][CH2:33][C:34]([NH:18][C:15]2[CH:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=4[C:2]([F:1])([F:23])[F:24])[CH2:11][CH2:10]3)=[CH:13][CH:14]=2)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCc1ccccc1)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridin-3-amine (225 mg, 0.7 mmol), 4-phenylbutyric acid (131 mg, 0.8 mmol), HATU (380 mg, 1.5 mmol) and DIPEA (465 μL, 2.7 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with diluted brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 40-70% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a light brown gum which solidified on standing. Swishing with hexanes-Et2O (1:1) gave the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C(NC(C)C)(C)C.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32]>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.[Cu]I.C1COCC1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.250 g, 0.718 mmol), Pd(PPh3)4 (0.083 g, 0.072 mmol), and copper(i) iodide (0.014 g, 0.072 mmol), was treated with 1 mL THF followed by diisopropylamine (1.535 mL, 10.77 mmol). The solution was degassed with argon and 3,3-dimethylbut-1-yne (0.295 g, 3.59 mmol) was added and the vial heated to 80° C. overnight. The reaction mixture was purified directly by column chromatography yielding (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:21])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])SC)[N:9]=1.[CH3:22][NH2:23]>C(O)C>[CH3:1][N:2]=[C:3]([NH2:21])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:23][CH3:22])=[N:18][C:19]#[N:20])[N:9]=1
Reactant: CN=C(N)Nc1nc(CCCCNC(=NC#N)SC)cs1
Reactant: CN
Solvent: CCO
Product: CN=C(N)Nc1nc(CCCCNC(=NC#N)NC)cs1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-methylguanidino)-4-[4-(3-cyano-2-methylisothioureido)butyl]thiazole (0.38 g.) in ethanol (10 ml.) was added 33% w/v ethanolic methylamine (40 ml.). The mixture was stirred overnight, evaporated to dryness and the residue triturated with water. The solid thus obtained was filtered and dried to give 2-(2-methylguanidino)-4-[4-(2-cyano-3-methylguanidino)butyl]thiazole, m.p. 119°-122° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][C:15]1[C:16]([CH3:30])=[C:17]([CH3:29])[C:18]2[O:22][CH:21]([CH2:23][CH2:24][CH2:25][I:26])[S:20][C:19]=2[C:27]=1[CH3:28].O>C1C=CC=CC=1>[Si:1]([O:14][C:15]1[C:16]([CH3:30])=[C:17]([CH3:29])[C:18]2[O:22][CH:21]([CH2:23][CH2:24][CH2:25][I:26])[S:20][C:19]=2[C:27]=1[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: c1ccccc1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCI)O2
Temperature: 50 °C

Procedure:
5.2 g of t-butyldimethylsilyl chloride and 4.6 g of imidazole were dissolved in 80 ml of benzene, and then the reaction mixture was heated for 1 hour at 50° C., after which a solution of 6.3 g of 5-hydroxy-2-(3-iodopropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Examples 74 and 75) in 10 ml of benzene was added and the reaction mixture was allowed to react for 8 hours at 40°-45° C. The reaction product was cooled, poured into water, and then extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography and the title compound was obtained from the fraction eluted with a 9:1 by volume mixture of cyclohexane and benzene.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([Cl:12])[C:3]=1[NH2:13].[F-].[Cs+].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([Cl:12])[C:3]=1[NH2:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: Nc1c(Br)cc(C(F)(F)F)nc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 150 °C
Yield: 17.5 %

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-pyridin-3-ylamine (84 g, 300 mmol) was stirred in 500 ml DMSO in the presence of caesium fluoride (46.3 g, 305 mmol) and benzylamine (66.6 ml, 610 mmol). The resulting brown suspension was heated at 150° C. for 16 h. Added to the cooled suspension was 1500ml water and the mixture extracted with 2×500 ml diethyl ether. The combined organic extracts were dried (MgSO4), concentrated in vacuo and purified by column chromatography on silica, eluting with Hept:EtOAc, 4:1 to 2:1 to give the title compound (15.8 g, 17%) as a pale brown solid. The undesired isomer was similarly isolated as a brown oil (51.0 g, 48%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH3:6])[OH:5])[CH3:2].C(N(CC)CC)C.C[Si](Cl)(C)C.[F:19][C:20]([F:26])([F:25])/[CH:21]=[CH:22]/[C:23]#[N:24]>O1CCCC1>[C:23]([CH2:22][CH:21]([P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2])[C:20]([F:26])([F:25])[F:19])#[N:24]
Reactant: N#C/C=C/C(F)(F)F
Reactant: CCOP(C)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)C(CC#N)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 2.16 g (20 mmol) of O-ethyl-P-methyl-phosphonous acid and 4.05 g (40 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is stirred under an atmosphere of argon at 25°. To this solution are added at 25° 4.35 g (40 mmol) of trimethylsilyl chloride over a period of 10 minutes. A white precipitate is formed. The reaction mixture is stirred at 25° for additional 16 hours. Then, 2.42 g (20 mmol) of 4,4,4-trifluorocrotononitrile, dissolved in 20 ml of dry tetrahydrofuran, are added at 25° over a period of 10 minutes. The reaction mixture is refluxed for 40 hours, cooled to 25°, poured into ice-water and extracted with dichloromethane. The extracts are combined, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to dryness. The crude product is chromatographed on 200 g of silica gel with trichloromethane as eluent. The product-containing fractions are combined and evaporated to give ethyl P-(3-cyano-1,1,1-trifluoro-prop-2-yl)-P-methyl-phosphinate as an oil.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])([CH3:3])[CH3:2].[CH2:21](N(C(C)C)CC1OC1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na].CS(C1C(C)=CC(O)=CC=1)(=O)=O>C(O)C>[CH2:21]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:16])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)N(Cc1ccccc1)CC1CO1
Reactant: Cc1ccc(S(C)(=O)=O)c(OCC(O)CNC(C)C)c1
Agent: Cc1cc(O)ccc1S(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(S(C)(=O)=O)c(OCC(O)CN(Cc2ccccc2)C(C)C)c1

Procedure:
A further modification of the procedure for preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing an epihalohydrin derivative of Formula VII containing a hydrogenolyziable blocking group follows. 1-[(N-Benzyl)isopropylamino]-2,3-epoxypropane is reacted with 4-(methylsulfonyl)-m-cresol sodium salt in ethanol to provide 1-[(N-benzyl)isopropylamino]-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:25][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O1CCOCC1.O>[F:25][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCc1cnc(-c2ccc(CCCCC)c(N)c2)nc1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCc1cnc(-c2ccc(CCCCC)c(F)c2)nc1
Reaction time: 1 h

Procedure:
56 g of 2-(3-amino-4-n-pentylphenyl)-5-n-hexylpyrimidine (m.p. 92°, obtainable by reaction of 2-(4-n-pentylphenyl)-5-n-hexylpyrimidine (c.p. 28.5°) with nitric acid to give 2-(3-nitro-4-n-pentylphenyl)-5-n-hexylpyrimidine (m.p. 41.5°) and hydrogenation on Raney nickel) is dissolved in 150 ml of dioxane at 50° and 208 ml of 35% tetrafluoroboric acid are added dropwise, with stirring. After one hour, the resulting emulsion is cooled to 0°, whereupon crystallization occurs. A solution of 20 g of sodium nitrite in 150 ml of water is added to the suspension and the mixture is stirred for one hour. The resulting mixture diazonium tetrafluoborate is filtered off with suction, washed with ice-water and dried. 5 g of the diazonium salt is heated at 200° until the evolution of gas has ended. 2-(3-Fluoro-4-n-pentylphenyl)-5-n-hexylpyrimidine of m.p. 30° is obtained by purification by chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1)(=[O:38])=[O:37]
Reactant: c1cnc2ccc(Cc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)n1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 6-[6-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline as prepared in Example 3 (10 mg, 0.03 mmol) and DIEA (9 μL, 0.05 mmol) in DCM (2 mL) was added methane sulfonylchloride (4 μL, 0.05 mmol). The reaction was stirred at rt overnight. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (3.1 mg, 31%) as a white solid. 1H-NMR (CD3OD): δ 9.06-9.00 (2H, q, J=5.3, 7.0 Hz), 8.89 (1H, s), 8.44 (1H, s), 8.29-8.10 (4H, m), 7.96-7.92 (1H, q, J=5.3, 3.0), 7.75-7.73 (1H, d, J=9.8 Hz), 4.87 (2H, s), 3.42 (3H, s). ESI-MS (m/z): Calcd. For C19H15N7O2S: 405.10; found: 406.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[F:23][C:24]([F:38])([F:37])[C:25]1[N:29]=[C:28]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[NH:27][N:26]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:24]([F:38])([F:37])[F:23])[N:29]=3)=[CH:31][CH:32]=2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
126 mg (purity 66%, 0.25 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 12.1D) and 64 mg (0.27 mmol) of 4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline (Example 1.1C) were reacted according to General Method 1. Yield: 76 mg (57% of theory)
Reaction SMILES: N.[Na].[C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:35]1[CH:39]=[C:38]([CH2:40]Cl)[N:37]=[CH:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.C1COCC1>[C:16]([N:35]1[CH:39]=[C:38]([CH2:40][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[N:37]=[CH:36]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(C(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccncc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere a 100 ml flask was charged with 50 ml liquid ammonia, a small piece of sodium and a few crystals of Fe(NO3)3. Then about 0.25 g (11 mmol) sodium metal was added and the mixture was stirred at ca. -70° C. for 0.5 hours. Then, under stirring, and at about -70° C. 1.69 g (10 mmoles) of phenyl-(4-pyridinyl)methane dissolved in 5 ml anhydrous ether are added in 10 minutes. After stirring for 0.5 hours the mixture was allowed to warm up to the boiling temperature of ammonia and 3.21 g (9 mmoles) of (3) dissolved in 20 ml anhydrous THF was added dropwise. The mixture was allowed to warm up to room temperature while ammonia evaporated. To the residue 30 ml water was added and the mixture was extracted with methylene chloride. Then the methylene chloride was evaporated from the dried, combined solutions yielding crude derivative (4) used as such in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.75 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>CN(C=O)C.N1C=CC=CC=1>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(F)cccc32)nc(N2CCOCC2)cc1=S

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 141 mg of 4-fluoro-2,3-dihydro-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH2:19]1[CH2:23]OC[CH2:20]1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[C:20]#[C:19][CH3:23])=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: C1CCOC1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Reaction time: 0.25 h

Procedure:
An oven-dried 3L 3-neck flask equipped with a mechanical stirrer, nitrogen inlet, nitrogen outlet and placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a separate oven-dried and nitrogen-flushed 500 mL RB flask, compound 1.1 (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with gentle warming. The solution of 1.1 was then added over 15 minutes. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes and then quenched with aqueous NH4Cl (0.6N, 750 mL) and diluted with hexanes (800 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH ˜2 with saturated aqueous KHSO4 and extracted with ethyl acetate (2×400 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (37 g, 91%). 1H NMR(500 MHz)(acetone-d6) δ 8.26 (s, 1H); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (br s, 1H); 4.46 (d, 1H, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s, 3H). MS ESI (pos.) m/e: 599.0 (2M+Na).