Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[NH:49]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[N:49]1([C:30]([C:29]2[CH:33]=[CH:34][C:26]([I:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: C1CCCNCC1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCCCCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and azepane and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C21H21IN4O3S, 536.0; m/z found, 535 [M−H]−. HPLC (reverse phase): RT=9.42 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.08 (d, J=1.8 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.81 (br s, 1H), 8.49 (d, J=7.3, 1H), 8.35 (d, J=8.4, Hz, 1H), 7.98 (s, 1H), 7.88 (t, J=8.1 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 3.30-3.27 (br m, 2H), 2.91-2.89 (m, 2H), 1.66-1.63 (m, 2H), 1.63-1.54 (m, 2H), 1.50-1.43 (br m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][C@H:12]2[CH2:16][C@@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[N:5]=[C:4]([NH:19]C(=O)C)[N:3]=1.[CH2:23](OC(OCC)OCC)[CH3:24].C(S(O)(=O)=O)C.C[N:40]([CH:42]=O)C>>[NH2:19][C:4]1[N:5]=[C:6]2[C:7]([N:8]=[CH:9][N:11]2[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:2]([NH:40][CH:42]2[CH2:24][CH2:23]2)[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(N[C@@H]2C=C[C@H](CO)C2)n1
Agent: CCS(=O)(=O)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 65 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
The title compound of Example 25 (0.91 g, 2.79 mmol) was dissolved in dry DMF (1 mL). Triethylorthoformate (10 mL) and ethane sulfonic acid (0.29 mL, 3.4 mmol) were added and the solution heated at 65° C. for 24 hours. The solution was evaporated to a syrup. The syrup was dissolved in 1N HCl (15 mL) and stirred for three hours. The pH was adjusted to 7 with 5N sodium hydroxide and the resulting mixture (oil formed) was extracted with i-propanol:chloroform/1:3 (3×100 mL). The combined organic layers were dried (MgSO4) and evaporated to a red glass (0.93 g). A solution of this glass in methanol (20 mL) was heated with cyclopropylamine (2 mL) in a Parr bomb at 70° C. for 18 hours. The resulting solution was evaporated to a dark glass which was adsorbed on silica gel. Elution with 7% methanol-ethylacetate gave title compound (148 mg, 19%) as white powder, after trituration with acetonitrile; 1H-NMR (DMSO-d6) identical with that of the title compound of Example 5.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1)(=O)C.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:23]=[C:22]([F:24])[C:20](=[O:21])[N:19]([CH:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[C:17]2=[O:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1CCCO1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c(F)cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
A 1.32 g quantity of N,O-bis(trimethylsiliyl)-acetamide was added with stirring to a suspension of 0.40 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 8 ml of dry dichloromethane at room temperature. To the mixture were added, after 4 hours, 0.32 g of 2-acetoxytetrahydrofuran and a solution of 0.1 ml of stannic chloride in 1.6 ml of dry dichloromethane. The mixture was stirred for 1.5 hours and neutralized with 0.64 ml of triethylamine and washed with water. The dichloromethane layer was concentrated and the residue was dissolved in 16 ml of methanol. To the solution was added 0.24 ml of acetic acid and the mixture was left to stand for 3 hours at 40° C. The solvent was distilled off and the residue was subjected to silica gel column chromatography to conduct a gradient elution using chloroform and mixtures of methanol (up to 4%) and chloroform, giving 0.3 g of the title compound in a yield of 77%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])CCC=C.[CH2:9]([O:25][C:26]1[CH:35]=[C:34](C)[CH:33]=[CH:32]C=1S([O-])(=O)=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O.O1CCCC1>[CH2:9]([O:25][CH2:26][CH:35]([CH2:34][CH:33]=[CH2:32])[CH2:3][OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCOc1cc(C)ccc1S(=O)(=O)[O-]
Reactant: C=CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCC(CO)COCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To a suspension of 19.1 g of 50% sodium hydride under argon in 300 ml of N,N-dimethylformamide is added dropwise over a period of 1 hour, with stirring a solution of 37 g of 4-penten-1-ol, 2-methanol (prepared as described by B. K. Wasson, et. al., J. Chem. Soc., 39, 923 (1961)) in 200 ml of tetrahydrofuran. After stirring another 30 minutes, 126.34 g of hexadecyloxytosylate is added followed by 500 ml of tetrahydrofuran. This mixture is stirred for 2.5 hours, then heated to 80° C. for 20 minutes and then at room temperature overnight. Water is added and the mixture extracted with ether. The ether extract is dried and then evaporated. The residue is distilled using a Kugelrohr. The fraction distilling at 200°-210° C. 1 mm is collected, purified by chromatography and then redistilled, to give 11.35 g of the desired compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>ClCCl>[CH:29]([O:28][C:26]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:27])([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 4-aminopiperidine-1-carboxylate (100 mg) and triethylamine (190 μL) are dissolved in dichloromethane (2 mL), treated with isopropyl chloroformate (920 μL, 1 M solution in toluene) and stirred for 2 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[CH:4]=[C:3]([Cl:9])[C:2]=1[O:10]CC(O)=O.ClC1C=C(Cl)C(Cl)=CC=1Cl.[OH-].[Na+:26]>CO>[CH:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[CH:4]=[C:3]([Cl:9])[C:2]=1[O-:10].[Na+:26]
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: Clc1cc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [O-]c1cc(Cl)c(Cl)cc1Cl

Procedure:
The usual starting material in the chemical synthesis of 2,4,5-T is 1,2,4,5-tetrachlorobenzene which can be reacted with methanol and sodium hydroxide in an autoclave under high temperature and pressure conditions to give the sodium salt of 2,4,5-trichlorophenol: ##STR2## 2,4,5-trichloroanisole is presumed to be an intermediate in this reaction. The high temperature and high pressure conditions of this step are also favorable for the production of a variety of other compounds from these starting materials. The choice of the proper temperature and pressure, and the control of these conditions throughout the reaction are critical for minimizing side reactions and hence impurities in the final product.
Reaction SMILES: C(OC([N:11]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.C(N(CC)CC)C>[F:51][C:47]1[CH:46]=[C:45]2[C:13]3([CH2:14][CH2:15][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:20])[CH2:17][CH2:18]3)[CH2:12][NH:11][C:50]2=[CH:49][CH:48]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccc(F)cc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Yield: 100.7 %

Procedure:
To a solution of 0.330 g of the intermediate obtained from Step A in 5 mL of ethanol at was added 1 drop of triethylamine and hydrogenated with hydrogen balloon for 3 h. The catalyst was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give 0.269 g of the product as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:9].N[C:21]1C=CC=C[CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[NH:15][C:19]1[CH:18]=[CH:17][CH:16]=[CH:22][CH:21]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(C1=C(N2CCCC2)CCC1)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(C1=C(Nc2ccccc2)CCC1)c1ccccc1Br

Procedure:
Reflux a solution of (2-bromophenyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]-methanone (14.1 g) (from Preparative Example 1) in benzene (100 ml) containing aniline (4.5 ml) and p-toluenesulfonic acid monohydrate (8.8 g) for 19 hrs. Remove water continuously with a Dean-Stark trap. Wash the cooled solution with water, 1M NaHCO3 solution, and with water. Dry the benzene solution, filter it, and evaporate the solvent. Crystallize to obtain (2-bromophenyl)[2-(phenylamino)-1-cyclopenten-1-yl]methanone, m.p. 106-5-108.5° from CH3CN.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:5]([CH:7]([CH3:11])[C:8]([OH:10])=O)=O.[CH2:16]=[O:17].[OH-].[Na+].Cl.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]([CH2:8][OH:10])[CH2:11][C:16](=[O:17])[NH:22][N:23]=2)[CH:12]=[CH:13][C:14]=1[NH2:15]
Reactant: C=O
Reactant: CC(C(=O)O)C(=O)c1ccc(N)c(Cl)c1
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)CC2CO)cc1Cl

Procedure:
45 g of 3-chloro-4-amino-benzoyl-propionic acid are stirred together with 50 ml of 35% formaldehyde solution and 440 ml of 0.5N sodium hydroxide solution for 17 hours at room temperature. The reaction mixture is adjusted with 2N hydrochloric acid to pH 5, and is extracted with ethyl acetate. The ethyl acetate phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The residue, 3-(3-chloroamino-benzoyl)-3-hydroxymethyl)-propionic acid, is directly further reacted unpurified by being refluxed together with 1600 ml of ethanol and 18 ml of hydrazine hydrate for 5 hours. The reaction mixture is concentrated by evaporation, and the residue is distributed between 4N hydrochloric acid and ethyl acetate. The aqueous phases are rendered basic with a 2N sodium carbonate solution, and are extracted with ethyl acetate. The ethyl acetate extracts are washed twice with 2N sodium carbonate solution and with water, dried and then concentrated by evaporation. As residue is obtained the crude 6-(3-chloro-4-amino-phenyl)- 5-hydroxymethyl-4,5-dihydro-3(2H)-pyridazinone, which together with 25 g of β,β-dibromodiethyl ether and 37 ml of diisopropylethylamine in 150 ml of dimethylformamide are refluxed for 18 hours. The reaction mixture is concentrated under high vacuum in a rotary evaporator; the residue is then taken up in ethyl acetate, and repeatedly washed with 1N hydrochloric acid and water. The organic phase is dried over sodium sulfate and concentrated by evaporation, the product which crystallises out being 6-(3-chloro-4-morpholino-phenyl)-5-hydroxymethyl-4,5-dihydro-3(2H)-pyridazinone, m.p. 172°-173° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[S:22]1(=[O:28])(=[O:27])[CH:26]=[CH:25][CH2:24][CH2:23]1.CO>C1COCC1>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:24]4[CH2:25][CH2:26][S:22](=[O:28])(=[O:27])[CH2:23]4)[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=S1(=O)C=CCC1
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1cc(OC2CCN(C3CCS(=O)(=O)C3)CC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (0.15 g, 0.53 mmol) in THF (5 ml) was added 2,3-dihydrothiophene 1,1-dioxide (commercially available, for example, from AKOS) (0.150 g, 1.27 mmol). The solution was heated to 80° C. for 2.5 h. To the solution at ambient temperature was added a further amount of 2,3-dihydrothiophene 1,1-dioxide (0.150 g, 1.27 mmol) and the solution stirred overnight at ambient temperature. The solution was heated to reflux for 2 h and then at ambient temperature for 7 days. The reaction was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes). The cartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo. The residue was purified by MDAP and the appropriate fractions combined and evaporated. The combined fractions were applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol. The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo to give the title compound (17 mg, 8%). LCMS RT=2.59 min, ES+ve m/z 403 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-Fluoro-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[C@@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: COC(=O)[C@H](C)Oc1cccc2cccnc12
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: C[C@H](Oc1cccc2cccnc12)C(=O)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a stirred mixture of (S)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (89.2 mg, 0.433 mmol). The mixture was stirred in a sealed tube in a microwave apparatus at 120° C. for 0.5 hour. After cooling to room temperature the solvent was evaporated, and the residue was first purified by prep-TLC and then prep-HPLC to afford the title compound (49 mg, yield: 28%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.86-8.97 (m, 1H), 8.38 (d, J=7.03 Hz, 1H), 7.51-7.67 (m, 3H), 7.30 (d, J=7.28 Hz, 1H), 7.06-7.13 (m, 3H), 6.98 (d, J=6.53 Hz, 1H), 5.07 (q, J=6.53 Hz, 1H), 4.10-3.88 (m, 1H), 3.65-3.76 (m, 2H), 3.43-3.51 (m, 1H), 3.35 (br. s., 1H), 2.86 (dd, J=16.06, 3.76 Hz, 4H), 2.62 (d, J=6.02 Hz, 2H), 1.71 (d, J=6.53 Hz, 3H). LCMS (m/z): 406.2 [M+H]+
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1.[NH2:20][C:21]1[C:26]([C:27](OCC)=[O:28])=[C:25]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[O:38][CH2:37][CH2:36][CH2:35]3)[C:24]([C:42]([O:44][CH3:45])=[O:43])=[C:23]([CH3:46])[N:22]=1>O1CCCC1>[NH2:20][C:21]1[C:26]([CH2:27][OH:28])=[C:25]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[O:38][CH2:37][CH2:36][CH2:35]3)[C:24]([C:42]([O:44][CH3:45])=[O:43])=[C:23]([CH3:46])[N:22]=1
Reactant: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc2c(c1)CCCO2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc(N)c(CO)c1-c1ccc2c(c1)CCCO2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
An ice cooled solution of Red-Al, 65 wt % solution in toluene (12.58 mL, 41.3 mmol) in tetrahydrofuran (THF) (188 mL) was treated with a solution of 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methylpyridine-3,5-dicarboxylate (7.64 g, 20.63 mmol) in tetrahydrofuran (THF) (31.4 mL) and the mixture was stirred at 0° C. for 5 minutes. The mixture was quenched with water (32 mL) then 15% NaOH (16 mL) was added. The mixture was warmed to ambient temperature and stirred for 20 minutes (solids formed). The mixture was filtered and then filtrate was concentrated. The residue was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and then concentrated to afford the crude methyl 6-amino-4-(chroman-6-yl)-5-(hydroxymethyl)-2-methylnicotinate as a light brown solid which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.87-6.72 (m, 3 H), 5.35-5.19 (m, 2 H), 4.50-4.41 (m, 2 H), 4.25-4.18 (m, 2 H), 3.50-3.45 (m, 3 H), 2.78 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.06-2.00 (m, 2 H); LC/MS (m/z) ES+=329.26 (M+1).
Reaction SMILES: [CH:1]1(OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([N:33]3[C:37]4[CH:38]=[C:39]([OH:42])[CH:40]=[CH:41][C:36]=4[N:35]=[CH:34]3)[S:28][C:29]=2[C:30]([NH2:32])=[O:31])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]([N:33]3[C:37]4[CH:38]=[C:39]([O:42][CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:40]=[CH:41][C:36]=4[N:35]=[CH:34]3)[S:28][C:29]=2[C:30]([NH2:32])=[O:31])[CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OC4CCCCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 59.6 %

Procedure:
To a mixture of 0.051 g (0.2 mmole) of toluene-4-sulfonic acid cyclohexyl ester, 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d) and 1 mL of dimethylformamide was added 0.163 g (0.5 mmole) of cesium carbonate. The mixture was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 40:60-100:0) to give 0.027 g of 4-(3-chloro-phenyl)-2-(6-cyclohexyloxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25) as a white powder. MH+/Z=453
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]=2[NH:24][C:25]2[C:26](=O)[CH2:27][CH2:28][CH2:29][CH:30]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1](/[N:5]=[C:26]1\[CH2:27][CH2:28][CH2:29][CH:30]=[C:25]\1[NH:24][C:13]1[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:16]=[CH:17][C:12]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCCC=C1Nc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: CCCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCC/N=C1\CCCC=C1Nc1c(-c2ccccc2)cccc1-c1ccccc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Follow a procedure similar to that of Preparation 2 except use n-butylamine (0.53 mL, 5.3406 mmol); toluene (7.0 mL); a solution of titanium(IV) chloride (0.1006 g, 0.5303 mmol) in toluene (3.0 mL); stir the resulting solution for 1 hour; then add a solution of 2-((1,1′:3′,1″-terphenyl)-2′-ylamino)-2-cyclohexen-1-one (0.3062 g, 0.9021 mmol, Preparation 7) in toluene (2.0 mL); toluene rinse (1.0 mL); to afford after isolation 0.3352 g (94.18%) of the product (J) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:22]N1C(=O)CCC1=O>CN(C)C=O.COC(C)(C)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([Br:22])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@H:16]([O:19][CH3:20])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: CO[C@H]1CC[C@H](n2c(=O)ccc3c(C)nc(N)nc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CO[C@H]1CC[C@H](n2c(=O)c(Br)cc3c(C)nc(N)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (482 mg, 0.1.67 mmol) in dimethylformamide (15 mL) was added N-bromosuccinimide (300 mg, 1.69 mmol). After stirring for 1 hour at room temperature the solution was diluted with methyltertbutylether and washed with 50% sodium carbonate (2×) and brine. The combined aqueous layers were extracted with dichloromethane. The combined organics were dried (MgSO4) filtered and concentrated. The solids were triturated with diethyl ether to afford 2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (594 mg, 97%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([OH:17])=O)[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:24]1([C:27](=[N:29]O)[NH2:28])[CH2:26][CH2:25]1>C(O)(=O)C>[CH:24]1([C:27]2[N:29]=[C:15]([C:5]3[CH:4]=[C:3]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:2](=[O:1])[N:7]4[C:6]=3[C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH:9]=[N:8]4)[O:17][N:28]=2)[CH2:26][CH2:25]1.[O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[CH:5][CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Reactant: NC(=NO)C1CC1
Solvent: CC(=O)O
Product: O=c1c(-c2ccccc2)cc(-c2nc(C3CC3)no2)c2c3sccc3cnn12
Product: O=c1c(-c2ccccc2)ccc2c3sccc3cnn12

Procedure:
The acid chloride prepared from 2.58 g of 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylic acid in accordance with Example 3a) is heated under reflux with 0.8 g of cyclopropanecarboxamide oxime in 50 ml of acetic acid until the reaction is complete. The solvent is removed in vacuo and the residue is chromatographed on silica gel. After recrystallization from ethyl acetate there are obtained 10-(3-cyclopropyl-1,2,4 oxadiazol-5-yl)-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine as yellow crystals of m.p. 201°-202° and 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine as yellow crystals of m.p. 242°-244° (acetonitrile).