Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:17][CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].CCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:17](\[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
4-Nitrobenzaldehyde (4.20 g) and (carbetoxyethylidene)triphenylphosphorane (10 g) were dissolved in toluene (36 ml), and the obtained mixture was stirred overnight under reflux conditions. After the obtained reaction mixture was allowed to cool, N-pentane (50 ml) was added thereto, and the produced white precipitate was filtered off. The filtrate was concentrated, and N-pentane (70 ml) was added to the residue. Then, ultrasonic waves were applied to the mixture. The produced precipitate was filtered off and dried under reduced pressure to obtain crude (E)-ethyl 3-(4-nitrophenyl)-2-methylacrylate as a yellow powder.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[NH:60][C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[NH:60]1[C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=[C:59]1[NH:58][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1[N+](=O)[O-]
Yield: 36.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 50 mg, 0.15 mmol), triethylamine (0.060 mL, 0.44 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (98 mg, 0.22 mmol), and 2-aminobenzimidazole (30 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 4 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (25 mg, 38%) as a pale yellow solid: mp 113-117° C.; EI-HRMS m/e calcd for C22H24N4O5S (M+) 456.1467, found 456.1465.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.O>CS(C)=O>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:14]([CH3:13])[CH2:19]2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C
Yield: 45.7 %

Procedure:
Heat a mixture of 1,4-dichlorophthalazine (7.80 g, 39.2 mmol), (S)-tert-butyl 2-methylpiperazine-1-carboxylate (4.98 g, 24.9 mmol) and triethylamine (10.3 mL, 73.9 mmol) in DMSO (110 mL) at 80° C. for 18 h. Pour the reaction mixture into water, rinsing with EtOAc. Extract with EtOAc. Wash the organic layer with water (2×) and brine, and dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 20% to 80% EtOAc in hexanes) to provide the title compound (4.13 g, 46%). ES/MS m/z (35Cl) 363.0 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]([C:19]([O:21]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1.[C:27]1([C:33]2[N:34]=[C:35]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[S:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:19]([N:41]2[CH2:40][CH2:39][CH:38]([C:35]3[S:36][CH:37]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:34]=3)[CH2:43][CH2:42]2)=[O:21])=[N:2]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1noc2ccccc12)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Yield: 47.5 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (277 mg, 0.573 mmol), 4-(4-phenyl-1,3-thiazol-2-yl)piperidine (280 mg, 1.15 mmol) and diisopropylethylamine (0.0998 ml, 0.573 mmol) in dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (110 mg, 47.4%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:16][CH2:15]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:15]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](OCCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-(4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless solid, MS: 468 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)C)(C)C.[CH3:28][O:29][CH2:30]/[CH:31]=[CH:32]/[C:33](Cl)=[O:34].C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:33](=[O:34])[CH:32]=[CH:31][CH2:30][O:29][CH3:28])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COC/C=C/C(=O)Cl
Agent: CC(C)N(C)C(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COCC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
To a stirred solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 0.62 g of diisopropyl methylamine in 21 mL of tetrahydrofuran at 0° C. was added 0.62 g of 4-methoxycrotonyl chloride. The mixture was stirred at 0° C. for 1.5 hr and 10 min at room temperature. The mixture was poured into saturated sodium bicarbonate-brine and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solution was filtered through silica gel and the solvent was removed. The residue was recrystallized from 1-butanol to give 1.25 g of 4-Methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a yellow solid: mass spectrum (m/e): M+H 415.0.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.[I-].[Na+].[Cl-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([N:10]([CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30](=[O:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)C1CCN(CCCl)CC1
Reactant: O=C(Nc1cccnc1)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)C1CCN(CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
In an atmosphere of argon, 4-nitro-N-(3-pyridyl)benzamide (973 mg, 4.00 mmol) was dissolved in DMF (10 ml) to which was subsequently added sodium hydride (176 mg, 60%, 4.40 mmol) at room temperature, stirred for 1 hour at 60° C., and added dropwise 1-(2-chloroethyl)-4-benzoylpiperidine (1.38 g, 5.49 mmol) and a catalytically effective amount of a DMF solution (12 ml) of sodium iodide. After 4 hours of stirring at 60° C., the reaction solution was mixed with saturated sodium chloride aqueous solution and extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium chloride aqueous solution and water in that order, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by recrystallization (ethyl acetate-ether) to obtain 439.6 mg (24.0%) of the title compound in a light yellow powder form.
Reaction SMILES: Cl.Cl[C:3]([Cl:15])([Cl:14])[CH2:4][CH:5]1[O:12][C:11](=[O:13])[CH2:10][C:6]21[CH2:9][CH2:8][CH2:7]2.CC[O-].[Na+].[OH-].[Na+]>C(O)C>[Cl:15][C:3]([Cl:14])=[CH:4][CH:5]1[C:6]2([CH2:7][CH2:8][CH2:9]2)[CH:10]1[C:11]([OH:12])=[O:13]
Reactant: O=C1CC2(CCC2)C(CC(Cl)(Cl)Cl)O1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C1C(C=C(Cl)Cl)C12CCC2
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Dry HCl is introduced into 2.57 g (0.01 mol) of the 5-(2',2',2'-trichloroethyl)-6-oxaspiro(3.4)-octan-7-one, produced according to Example 11, in 30 ml of absolute ethanol. After the reaction has subsided (temperature rise up to 55° C.), the reaction mixture is concentrated by evaporation; it is then taken up in absolute ethanol, and 0.011 mol of sodium ethylate (produced from 0.27 g of sodium in ethanol) is added. After a stirring period of 30 minutes, the mixture is concentrated by evaporation; 38 ml (about 0.06 mol) of 10% sodium hydroxide solution is added, and stirring is maintained at 95° C. for 6 hours. After cooling, the mixture is washed with several portions of diethyl ether, acidified with sulphuric acid, and extracted with diethyl ether. The ether extracts after drying over sodium sulphate are concentrated by evaporation. By filtration of the residue from the ten-fold amount by weight of silica gel (eluant: hexane/diethyl ether in the volume ratio of 1:1), a small amount of strongly polar impurities is removed. After concentration of the filtrate by evaporation, there is obtained 2-(2',2'-dichlorovinyl)spiro(2.3)hexane-1-carboxylic acid of the formula ##STR15## having a melting point of 122°-128° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12]C=O)[CH2:4][CH2:3]1.[ClH:15]>C(O)C>[ClH:15].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: O=CNC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: CCO
Product: NC1CCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 19.6 g. of N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)formamide in 214 ml. of 95% ethanol and 214 ml. of 2N hydrochloric acid is heated at reflux for 3 hours and then stirred at room temperature for 2 days. The solution is filtered and the filtrate concentrated in vacuo to afford a dark residue. The residue is dried by adding ethanol and evaporating the mixture in vacuo. This procedure affords 20.2 of the title compound, melting point 200°-216° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][OH:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][O:23][C:30](=[O:32])[CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide (prepared in Example 67, 102 mg, 0.27 mmol) was dissolved in pyridine (2 mL) and acetic anhydride (27 umL, 0.29 mmol) was added. The reaction stirred at 25° C. for 16 h. The solution was diluted with ethyl acetate (40 mL), washed with aqueous 1.0 M hydrochloric acid solution (3×15 mL), saturated aqueous brine solution (1×10 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded acetic acid 2-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-ethyl ester (78 mg, 60%) as a white foam: ESI-LRMS m/e calcd for C22H28ClN3O5S [M+] 481.1, found 482.3 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2 H, CH2), 1.39-1.79 (m, 8H, 4×CH2), 1.95 (s, 3H, COCH3), 2.01-2.19 (m, 1H, CH), 3.33 (s, 3H, SO2CH3), 3.86-3.95 (m, 1H, CH), 4.18-4.24 (m, 2H, OCH2), 4.29 (t, J=5.0 Hz, Hz, 2H, NCH2), 6.43 (d, Jo=2.3 Hz, 1H, Ar), 7.55-7.61 (m, 2H, Ar), 7.68 (d, Jm=1.7 Hz, 1H, Ar), 7.99 (d, Jo=8.2 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.[OH-].[K+]>CO>[C:1]([C:3]1[C:4]([OH:5])=[N:6][C:7]([OH:12])=[CH:8][C:9]=1[CH3:11])#[N:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)nc(O)c1C#N
Temperature: 25 °C
Yield: 76.6 %

Procedure:
Cyanoacetamide (8, 34 g, 0.40 mol) and ethyl acetoacetate (9, 52 g, 0.40 mol) were dissolved in methanol (250 mL) at room temperature, a solution of potassium hydroxide (28 g, 0.42 mol) in methanol (200 mL) was slowly added, and the resulting mixture was heated to reflux for 12 h. The reaction mixture was cooled to room temperature and the white amorphous precipitate was filtered and washed with methanol (2×50 mL). The solid product was redissolved in hot water. The solution was carefully acidified and the off-white precipitate was allowed to form. The precipitate was filtered and washed with water and methanol to yield 110 (46 g, 75%): mp>300° C. (dec) [lit. (J. Org. Chem. 1960, 25, 560-564.) mp 315-320° C. (dec)]. 1H NMR (300 MHz, DMSO-d6) δ 5.58 (s, 1H), 2.22 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH:43]1[CH2:46][O:45][CH2:44]1>CN(C=O)C.O>[CH3:23][S:20]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[CH:10]1[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:2](=[O:1])[N:11]1[CH2:42][CH:43]1[CH2:46][O:45][CH2:44]1)[C:16]#[N:17])(=[O:22])=[O:21]
Reactant: BrCC1COC1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC1COC1
Temperature: 50 °C

Procedure:
To a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methanesulfonyl-benzonitrile (INTERMEDIATE 18, 150 mg, 0.28 mmol) in DMF (3.0 mL) is added cesium carbonate (178 mg, 0.55 mmol) and 3-bromomethyl-oxetane (83 mg, 0.55 mmol) and the mixture is stirred at 50° C. over night. The reaction mixture is diluted with DMF and water and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 35.5 mg; ESI mass spectrum [M+H]+=560; Retention time HPLC: 1.04 min (Z018_S04).
Reaction SMILES: ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:40][C:41]1[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][N:42]=1.C(N(CC)CC)C.ClC1C=C(Cl)C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=1>ClCCCl>[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([NH:47][C:45]3[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=3)=[O:28])=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1ccnc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccnc(F)c1)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(O)c1cnc2c(Cl)cc(Cl)nn12
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(Br)cc(Cl)nn12
Temperature: 70 °C
Reaction time: 14 h
Yield: 103.5 %

Procedure:
A ˜1:1 mixture of 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid 1D (2.0 g, 8.62 mmol) was suspended in DCE (20 mL), and treated with neat oxalyl dichloride (4.37 g, 34.5 mmol) followed by N,N-Dimethylformamide (0.534 mL, 6.90 mmol). The reaction mixture was heated at 70° C. for 6 hours, concentrated and dried under high vacuum for 1 hr and taken to the next step without further purification. The crude mixture of acid chloride was suspended in DCM (10 mL) and treated with 2-fluoropyridin-4-amine (1.0 g, 8.92 mmol) and triethylamine (3.75 mL, 26.8 mmol) and stirred at room temperature for 14 hours. The reaction mixture was filtered through a Buchner funnel, and washed with water (2×25 mL) to isolate 1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (1.18 g, 8.92 mmol, 40.5% yield) as yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.47 (M+H=326.1 and M+H=372.04).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]([NH:20][OH:21])([CH3:19])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:20]([CH:17]([CH3:19])[CH3:18])[OH:21])[N:3]=1)[CH2:14][CH3:15]
Reactant: CC(C)NO
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(O)C(C)C)n1
Yield: 61 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and N-isopropyl-hydroxylamine hydrochloride were reacted as described in Example 13 to yield N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV) (61% yield). ESI-MS (m/z): 269 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:11]3[NH:12][N:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[C:33]([N:12]1[C:11]2=[C:20]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]2[CH2:15][CH2:14][N:13]1[CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)CN1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)N1c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCN1CC(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-2-isobutyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (70 mg, 0.199 mmol) and pyridine (31 mg, 0.398 mmol) in N-methyl-2-pyrrolidone (1.2 ml) was added acetyl chloride (19 mg, 0.239 mmol) in N-methyl-2-pyrrolidone (0.3 ml) at ambient temperature. The reaction mixture was stirred for 1 hour, then aqueous saturated sodium bicarbonate and ethyl acetate were added thereto. The organic phase was separated, and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol; 100/1~40/1). The fractions containing the object compound were concentrated in vacuo and the obtained oil was crystallized from diisopropyl ether to give 1-acetyl-7-(4-fluorophenyl)-2-isobutyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo-[5,1-c][1,2,4]triazine (57.0 mg).
Reaction SMILES: [H-].[Li+].[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[NH:9][CH:8]=1)=[O:6].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[N:9]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Agent: Br
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2cccnc2)c(=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium hydride (14 mg, 1.64 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.190 g, 0.529 mmol) in DMF (5 mL) at 0° C. After stirring for 30 minutes, 3-bromomethyl-pyridine hydrobromide (0.14 g, 0.53 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. After quenching with ice water, the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (1% MeOH in methylene chloride) yielded 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylic acid methyl ester. The methyl ester was dissolved in 4:1 THF:MeOH (5 mL) and 1 M LiOH solution (1.1 mL) was added. After 1 hour, the reaction mixture was acidified to pH 1 with 10% aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Trituration with diethyl ether gave 0.160 g (69% two step yield) clean desired product. MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 9.40 (bs, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.51 (d, 1H), 7.74 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.16 (m, 1H), 0.525 (s, 1H).