Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH:10](=[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CC=Cc1ccccc1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: O
Product: O=C1NC(=O)C(=CC=Cc2ccccc2)C(=O)N1
Yield: 95.3 %

Procedure:
Barbituric acid (10.0 g) was dissolved in water (150 ml) at reflux, and the solution was stirred vigorously and maintained at just below refluxing point while freshly distilled cinnamaldehyde (10.3 g) was added slowly: a yellow precipitate formed almost immediately. After the addition, the mixture was stirred and maintained at just below refluxing point for 1 hour to complete the reaction. The product was filtered off, washed several times with hot water and then with cold ethanol, and then dried to give yellow 5-cinnamylidenebarbituric acid (18 g, 96% theoretical yield) m.p. 268°-70° (decomp).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:19]=[CH:18][C:14](C(O)=O)=[C:13]([F:20])[C:12]=3[Cl:21])=[CH:6][C:5]=12.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:19]=[CH:18][C:14]([NH2:24])=[C:13]([F:20])[C:12]=3[Cl:21])=[CH:6][C:5]=12
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial was charged with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoic acid (0.090 g, 0.2925 mmol), triethylamine (0.1223 ml, 0.8776 mmol) and DMF (1.5 ml). Diphenylphosphoryl azide (0.1630 ml, 0.7313 mmol) was added. The reaction was stirred at ambient temperature for 3 hours, then water (0.2199 ml, 0.2925 mmol) was added. The vial was sealed and heated to 100° C. for 1 hour, then cooled to ambient temperature and poured into 1 N NaOH/ice. The reaction was extracted with EtOAc, and the organic layer was dried, filtered and concentrated. The residue was purified by flash chromatography, eluting with a gradient from 100% EtOAc to 10% (with 6% NH4OH) MeOH/EtOAc.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:17][C:16]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.[CH:24](=[N:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[CH:24](=[N:31][CH2:32][CH:33]1[CH2:34][CH2:35][N:36]([CH2:11][C@@H:12]2[O:17][C:16]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:37][CH2:38]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(Br)cc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(c1)O[C@@H](CN1CCC(CN=Cc3ccccc3)CC1)CO2
Reaction time: 24 h

Procedure:
A mixture of (R)-7-bromo-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (6.5 g, prepared as described in WO97/03071), N-benzylidene-4-piperidylmethylamine (3.0 g), potassium carbonate (4.1 g), and potassium iodide (10 mg) in acetonitrile (200 ml) was heated at reflux, with stirring, under nitrogen for 24 hours. The reaction was cooled, filtered and concentrated under reduced pressure to afford (S)-N-benzylidene-1-[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine (6.3 g) as an orange-brown viscous oil.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C(OO)(=[O:20])C>C1(C)C=CC=CC=1>[CH2:1]([N+:5]1([O-:20])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: CC(=O)OO
Solvent: Cc1ccccc1
Product: CC(C)C[N+]1([O-])C=Nc2cnc3ccccc3c21

Procedure:
The oxidation of 1-isobutyl-1H-imidazo[4,5-c]quinoline produced in Example 3 is carried out in toluene at 40-45° C. using peracetic acid as oxidant to produce 1-isobutyl-1H-imidazo[4,5-c]quinoline N-oxide. The product is isolated by filtration after addition of a sodium sulfate solution and ammonium hydroxide.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([CH2:10][C:11]([O:13]CC)=O)[NH:9][C:5]=2[CH:4]=1.[C:19](#[N:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22]>>[CH3:18][N:2]([CH3:1])[C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([CH2:10][C:11]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]#[N:27])=[O:13])[NH:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)Cc1nc2ccc(N(C)C)cc2[nH]1
Reactant: N#Cc1ccccc1N
Product: CN(C)c1ccc2nc(CC(=O)Nc3ccccc3C#N)[nH]c2c1

Procedure:
The title compound was synthesized as described in Example 9, Method B using ethyl 2-[5-(dimethylamino)benzimidazol-2-yl]acetate and anthranilonitrile. LC/MS m/z 320.2 (MH+), Rt 1.68 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH:43]1[CH2:48][CH2:47][O:46][C@@H:45]([CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:44]1>CN(C)C=O>[C:53]([O:52][C:51](=[O:57])[NH:50][CH2:49][C@@H:45]1[O:46][CH2:47][CH2:48][N:43]([C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[CH2:44]1)([CH3:56])([CH3:54])[CH3:55]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.432 g), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl(2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:13])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:2]=[CH2:3].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[O:13][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCOc1cc(O)cc(OC)c1
Product: C=CCOc1cc(OC)cc(Oc2ccc(C=O)cc2)c1

Procedure:
The product from Example 90A and 4-fluorobenzaldehyde were processed as in Example 61C to provide the title compound. MS (DCI) m/z 285 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:6][CH:7]=[CH2:8])[CH3:2].CCN(C(C)C)C(C)C.[C:25]([C:27]1[CH:28]=[C:29]([C:37](Cl)=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([C:37]([N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:6][CH:7]=[CH2:8])=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]
Reactant: C=CC[C@H](CNCC)c1ccc(F)cc1
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@H](CN(CC)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(2S)-N-Ethyl-2-(4-fluorophenyl)pent-4-en-1-amine (0.13 g, 0.63 mmol) was dissolved in CH2Cl2 and to the solution were added DIPEA (0.18 g, 1.4 mmol) and then 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 0.15 g, 0.66 mmol) dissolved in CH2Cl2 (2 mL). The mixture was stirred for 2 h at room temperature and then diluted with CH2Cl2. The solution was washed with water, aqueous KHSO4 (10 mL, 1M) and brine. The solvent was removed by evaporation after the solution had been dried. The product was purified by chromatagraphy on silica gel using a gradient of methanol-CH2Cl2 (0% methanol-5% methanol). There was obtained 0.13 g (53%) of 3-cyano-N-ethyl-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Temperature: 130 °C
Yield: 100 %

Procedure:
To a solution of 6-(trifluoromethyl)-3-pyridinol (2 g, 12.26 mmol) and 4-fluorobenzaldehyde (1.315 ml, 12.26 mmol) in DMF (50 mL), was added K2CO3 (2.54 g, 18.39 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.28 g, 12.26 mmol, 100% yield) as a brown oil. LCMS: rt=3.16 min, [M+H+]=268
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O[CH:12]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Product: CC(=O)c1ccccc1OC(CCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(2-hydroxyphenyl)ethanone and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 527.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH:10]([NH2:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH:13][CH:10]([CH3:12])[CH3:11]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CC(C)Nc1c(Cl)cnnc1Cl

Procedure:
A solution of 3,4,5-trichloropyridazine (9.2 g) and isopropylamine (16.5 g) in toluene (25 ml) is refluxed for 18 hr. Excess isopropylamine is removed by atmospheric distillation. The residual solution is cooled and diluted with dichloromethane and aqueous sodium hydroxide solution (5%). The phases are separated. The organic phase is washed with water and then with saline. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give a liquid which contains a mixture of isomeric products. The isomers are separated by flash chromatography on silica gel eluting with ether/hexane (30/70). The appropriate fractions are pooled and concentrated to give the desired isomer, NMR (CDCl3) 1.33, 4.59, 4.87 and 8.60 δ; CMR (CDCl3) 24.2, 46.4, 117.1, 139.3, 145.5 and 151.3 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:21][CH2:20][C:13]3[N:14]=[CH:15][N:16]=[C:17]([O:18]C)[C:12]=3[CH2:11]2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:21][CH2:20][C:13]3[N:14]=[CH:15][N:16]=[C:17]([OH:18])[C:12]=3[CH2:11]2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N2CCc3ncnc(OC)c3C2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(N2CCc3ncnc(O)c3C2)cc1Cl
Temperature: 90 °C
Yield: 99.2 %

Procedure:
To 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (intermediate 15)(95 mg, 0.31 mmol) in MeOH (5.0 mL) in a glass vial was added 2M NaOH(aq) (3.0 mL). The vial was capped and heated at 90° C. for 24 h. Acidified with glacial AcOH to pH 6, evaporated in vacuo and the residue extracted with CH2Cl2 (1×50 mL with stirring). With each extraction, the CH2Cl2 layer was decanted from the solid residue. The CH2Cl2 layers were combined. The solid residue was then washed with water (10 mL) and filtered. This filtered solid was combined with the CH2Cl2 layers and evaporated in vacuo to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol as a yellow solid (90 mg, 107% yield) LCMS: [M+H]+=293.0/294.8, Rt(3)=1.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>>[NH:25]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:18])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]3[N:10]([CH:22]=[CH:23][N:24]=3)[C:11]=2[N:12]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=c1c2cnc(Nc3ccccc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (70.0 mg, 0.195 mmol) and aniline (39.1 μl, 0.428 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with saturated NaHCO3/brine and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (8:2 to 7:3) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (d, J=1.83 Hz, 1H), 7.14 (t, J=7.48 Hz, 1H), 7.42 (t, J=7.63 Hz, 2H), 7.54-7.59 (m, 2H), 7.61-7.66 (m, 1H), 7.70-7.74 (m, 1H), 7.79-7.90 (m, 3H), 9.14 (s, 1H), 10.78 (s, 1H). MS (ESI+) m/z 389.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22]C)=[C:5]([OH:14])[C:6](=[O:13])[NH:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22])=[C:5]([OH:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(Cl)cc1-c1c(O)c(=O)[nH]c2cc(Cl)cc(Cl)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(-c2cc(Cl)ccc2O)c1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a suspension of 5,7-dichloro-4-(5-chloro-2-methoxyphenyl)-3-hydroxy-2(1H)-quinolinone (2.22 g, 6.0 mmol) [prepared in Example 1] in methylene chloride was added BBr3 (30 mL, 1.0M solution in methylene chloride, 5.0 equiv.) at -78° C. and the suspension became a clear solution. The solution was stirred under an argon atmosphere at -78° C. for 3 hours then at room temperature for an additional 20 hours. Distilled water (0.5 mL) was added dropwise and stirring continued for 10 minutes. The reaction mixture was evaporated under vacuum and the solid residue was suspended in water (100 mL), sonicated for 5 minutes then stirred for 10 minutes, filtered, washed with water (3×30 mL) and dried to yield 2.15 g (≈100%) of the title compound as a white solid: mp=297°-299° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CCC2

Procedure:
A solution of 2 g (0.0105 mole) 7-nitro-1-tetralone in 120 ml ethanol was hydrogenated under <5 psi H2 pressure using Raney Ni as catalyst. The solution was filtered with the aid of super gel and concentrated under reduced pressure to give the 7-amino-1-tetralone.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Br.[NH2:8][C:9]1[N:10]=[C:11]([Br:14])[S:12][CH:13]=1.C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[Br:14][C:11]1[S:12][CH:13]=[C:9]([NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[N:10]=1
Reactant: Nc1csc(Br)n1
Reactant: CC(C)C(=O)Cl
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1csc(Br)n1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of isobutyryl chloride (4.15 ml, 40 mM) in pyridine (50 ml) was cooled to 0° C. and treated portionwise with 4-amino-2-bromothiazole hydrobromide (7.8 g, 30 mM). After stirring for 1 h. the reaction mixture was poured onto 20% aqueous sodium acetate solution (500 ml) and extracted with chloroform (3×200 ml). The combined organic layers were dried and the solvents removed under reduced pressure to yield an oil which eventually crystallised. Recrystallisation from 60°-80° petroleum ether gave the title compound (2 g, 20%). mp: 95° (Found: C, 34.1; H, 3.8; N, 11.3. C7H9BrN2OS requires C, 33.7; H, 3.6; N, 11.2%).
Reaction SMILES: C(OC([NH:8][C@@:9]1([CH3:37])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([NH:29][NH:30][C:31]([S:33][CH3:34])=[S:32])=O)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:36])[CH3:35])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:8][C@@:9]1([CH3:37])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]4[S:32][C:31]([S:33][CH3:34])=[N:30][N:29]=4)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21]([NH2:22])=[O:23])[C:10]1([CH3:35])[CH3:36]
Reactant: CSC(=S)NNC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(N)C4(C)C)c(C(N)=O)cnn3c2)s1
Yield: 208.2 %

Procedure:
A solution of methyl 2-(4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioate (466.5 mg, 0.849 mmol) and p-toluenesulfonic acid monohydrate (404 mg, 2.122 mmol) in ethanol (4 mL) was heated to 120° C. for 50 minutes. The reaction mixture was concentrated to yield 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (763 mg, 94% yield). MS (ES+) m/z: 432.08 (M+H); HPLC retention time: 2.493 min (analytical HPLC Method F).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:22].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:10]3[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=3[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=2[CH3:22])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(O)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2c(c(Oc3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Temperature: 140 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
A mixed solution of N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.36 mmol) obtained in Example 343, 4-isopropylphenol (556 mg, 4.08 mmol) and potassium carbonate (188 mg, 1.36 mmol) in pyridine (16 mL) was stirred at 140° C. under argon atmosphere for 1 hour. Copper iodide (259 mg, 1.36 mmol) was added to the reaction solution and the mixture was stirred at 140° C. for 60 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with 1 N hydrochloric acid and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) and Gilson HPLC to obtain 230 mg (yield: 40%) of the title compound. Melting point: 148-149° C. (ethyl acetate-hexane).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:11].Cl[O-].[Na+]>O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][NH2:11]
Reactant: Sc1nc2ccccc2s1
Reactant: N
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: NSc1nc2ccccc2s1

Procedure:
2-Benzothiazole sulfenamide was synthesized from the reaction of 2-mercaptobenzothiazole, ammonia, and sodium hypochlorite in water (previously incorporated J. Org. Chem., 14, 921 (1940)).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([CH3:17])[CH2:5]1)(=[O:3])[CH3:2].[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:17][C@H:6]1[NH:7][CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]1
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 137.6 %

Procedure:
A mixture of (R)-tert-butyl 4-acetyl-2-methylpiperazine-1-carboxylate (1.34 g, 5.53 mmol) and TFA (10 mL, 130 mmol) in DCM (30 mL) was stirred at rt for 45 min, then concentrated, diluted with DCM, and then concentrated again which was repeated 3 times. Dried under high vacuum at 80° C. to give (R)-1-(3-methylpiperazin-1-yl)ethanone 2,2,2-trifluoroacetate (1.95 g). MS (ESI+) m/z 143.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O.CCOCC>[CH2:33]([C:18]([CH:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:27]([O-:29])=[O:28])([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[CH3:34]
Reactant: CCI
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Yield: 108.2 %

Procedure:
[2-(5-Chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (15.29 g, 36.25 mmole) was dissolved in dry dimethylformamide (100 ml) under argon. Prewashed (ether, 3 times), 50% sodium hydride (1.04 g, 43.3 mmole) was added with stirring. (The mixture turned from yellow to a dark red color). Stirring was continued for 20 minutes before iodoethane (14.5 ml, 28.3 g, 181 mmole, 5 eq) was added dropwise, and the reaction mixture was allowed to stir for an additional 2 hours. The solution was diluted with ether and washed with water. The organic layer was dried (magnesium sulfate), concentrated, and vacuum-dried overnight to yield 17.65 g of crude product as a light yellow oil. This material was triturated with methanol leaving 12.73 g of white solid, melting point 95.5°-97.0° C. Additional product was present in the mother liquor.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(Br)cc1
Product: O=C(c1cnoc1-c1ccc(Br)cc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(4-bromophenyl)isoxazole-4-carboxylic acid (13.4 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (16.2 mg). MS (pos) m/z 321.0.