Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]([O:24]CC)=O)[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.CO.[NH3:29]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]([NH2:29])=[O:24])[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(-c2ccc(OCc3cccc(F)c3)cc2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc(-c2ccc(OCc3cccc(F)c3)cc2)n1

Procedure:
A solution of ethyl 6-(4-{[(3-fluorophenyl)methyl]oxy}phenyl)-2-pyridinecarboxylate (D3, 110 mg, 0.30 mmol) in MeOH/NH3 (7M, 5 ml) was stirred at 60° C. in a sealed tube for 6 h. The solvent was then evaporated under reduced pressure to afford the title compound (95 mg); MS: (ES/+) m/z: 323 [MH+], C19H15FNO3 requires 322; 1H-NMR (300 MHz, DMSO) δ (ppm): 8.25 (bs, 2H), 8.20 (d, 1H), 8.05 (d, 1H), 7.95 (t, 1H), 7.85 (d, 1H), 7.65 (bs, 1H), 7.40 (t, 1H), 7.30 (d, 2H), 7.15 (t, 1H), 7.10 (d, 2H), 5.20 (s, 2H).
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br/[CH:42]=[CH:43]/[CH2:44][C:45]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])([CH3:47])[CH3:46].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4]/[CH:42]=[CH:43]/[CH2:44][C:45]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])([CH3:47])[CH3:46])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:18]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/Br
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[Si](CC)(CC)OC(C)(C)C/C=C/SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (304 mg, 0.504 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene (296 mg, 1.01 mmol), a 1M potassium hydroxide methanol solution (3 ml) and tetrahydrofuran (2 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (at room temperature for 10 min.), worked up and purified by column chromatography (hexane:toluene=6:1) to give the titled compound (351 mg, 90%) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH3:2])[CH3:22]
Reactant: C[C@H]1CCCN1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCN1CCC[C@@H]1C
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(S)-2-methyl-pyrrolidine hydrochloride (0.8 g, 6.6 mmol, 1.1 eq) was dissolved in 2-butanone (20 mL) and potassium carbonate (1.7 g, 12.6 mmol, 2.1 eq) was added. Ethyl 4-bromobutyrate (0.86 mL, 6.0 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature and any solid present was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give 1.20 g of the title compound (yield 99%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:8][CH2:7][CH2:6][N:5]([C:9](=O)[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:3]1=2.Cl>O1CCCC1>[CH3:1][C:2]1([CH3:24])[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:4]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:3]1=2
Reactant: CC1(C)CCCN(C(=O)CN2CCCC2)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCCN(CCN2CCCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 70 °C

Procedure:
1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2-pyrrolidin-1-yl-ethanone (0.508 g, 0.00153 mol), 1.00 M of Borane-THF complex in tetrahydrofuran (7.7 mL; Acros) and anhydrous tetrahydrofuran (12.4 mL) were combined in a round bottom flask and heated to 70° C. for 6.5 hours. Concentrated HCl was added dropwise until gas evolution stopped. Solvent was removed under reduced pressure, then an additional 5 mL of conc. HCl was added until the mixture was pH 1. The reaction was heated at 100° C. for 1.5 hours. The reaction was removed from the heat and 10 N NaOH (6 mL) was added until the mixture was pH 7-8. Na2CO3 was added until the solution was pH 11. The solution was extracted twice into DCM, and the combined organic layers were dried with sodium sulfate, filtered and concentrated under reduced pressure to yield a crude brown oil, 5,5-Dimethyl-8-nitro-1-(2-pyrrolidin-1-yl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine. LCMS: m/z=332.35 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:14]2[C:19]([CH:20]=[C:21]3[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]3)=[CH:18][CH:17]=[CH:16][CH:15]=2)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[CH:25]1[C:26]2[C:21](=[CH:20][C:19]3[C:14]([C:13]=2[CH2:12][NH:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCCNCc1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CCO
Product: NCCCNCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of 12a (200 mg, 0.51 mmole) was dissolved in absolute ethanol (6 mL) and stirred at 0° C. for 10 minutes. A 4N HCl solution (10 mL) was added to the reaction mixture dropwise and stirred at 0° C. for 20 minutes and then at room temperature overnight. The solution was concentrated in vacuo to give 16 as a yellow solid in 90% yield. 1H NMR (CD3OD) δ 8.69 (s, 1H), 8.39 (d, 2H), 8.15 (d, 2H), 7.74 (m, 2H), 7.60 (m, 2H), 5.33 (s, 2H), 3.45 (t, 2H), 3.12 (t, 2H), 2.23 (q, 4H); 13C NMR (CD3OD): δ 6 132.6, 132.0, 131.6, 130.6, 129.0, 126.7, 124.0, 122.5, 46.6, 44.6, 38.1, 25.4. HRMS (FAB) calcd for C18H20N2.2HCl (M+H−2HCl)+ 265.1699, Found 265.1704.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: ClCc1nc2ccccc2o1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2nc3ccccc3o2)c1
Yield: 44.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (189 mg, yield: 44.8%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]2[CH2:11][C:12](=[CH:20][CH2:21][CH2:22][Br:23])[C:13]3[C:14]([O:19][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N:15][CH:16]=[CH:17][CH:18]=3)=O.[NH2:24][C:25]([NH2:27])=[S:26].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:27][C:25]1[S:26][CH:2]=[C:3]([C:5]2[C:10]3[CH2:11][C:12](=[CH:20][CH2:21][CH2:22][Br:23])[C:13]4[C:14]([O:19][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[N:15][CH:16]=[CH:17][CH:18]=4)[N:24]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccc2c1CC(=CCCBr)c1cccnc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cccc3c2CC(=CCCBr)c2cccnc2O3)cs1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of the product of step 1 (1.1 g) in ethanol (11 ml) was added thiourea (193 mg) at room temperature, and the mixture stirred at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodiumbicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 7-(2-aminothiazol-4-yl)-5-(3-bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridine (749 mg).
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].OO.C(=O)([O-])[O-:33].[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1([C:28]([NH2:29])=[O:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC1(C(N)=O)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (36 mg) obtained in Example 2 in dimethylsulfoxide (1 mL) were added a solution of 30% aqueous hydrogen peroxide (28 μL) and 2M aqueous potassium carbonate (0.14 mL), and the mixture was stirred overnight at room temperature. Water was added thereto in an ice bath, and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized (diisopropyl ether/ethanol) to give the title compound (13 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:30][C:31]#[N:32]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][C:31]#[N:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CC#N)CC1
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Combine 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (2.55 mmol; 969 mg), tetra-N-butylammonium bromide (0.26 mmol; 82 mg), 50 wt % aq sodium hydroxide (8.42 mmol; 0.45 mL) and DCM (25 mL). Add bromoacetonitrile (5.11 mmol; 0.36 mL) dropwise over 10 min. Stir 45 min and dilute with DCM, wash with brine, 50% saturated aqueous sodium chloride solution, dry over MgSO4, filter and evaporate. Purify over 150 g silica gel with 20% EA/DCM to provide the title compound (812 mg; 76%). MS (ES): m/z=419 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][C@@H:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][N:21]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][C@@H:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH2:22][N:21]2[C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:19])[O:14][N:13]=1)([CH3:1])[CH3:11]
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)Nc2cc(C(C)(C)COC3CCCCO3)no2)N(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)Nc2cc(C(C)(C)CO)no2)N(c2ccc(Cl)cc2)C1

Procedure:
A solution of (2S,4R)-4-tert-Butoxy-1-(4-chloro-phenyl)-pyrrolidine-2-carboxylic acid {3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-amide (123 mg, 0.237 mmol) and pyridinium p-toluenesulfonate (20 mg, 0.047 mmol) in ethanol (2 mL) is heated at 55° C. for 42 hours. After this time, the reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, m/z 436 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:27]1
Reactant: OCCCN1CCOCC1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(O)ccc2c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cnc2cc(OCCCN3CCOCC3)ccc2c1=O
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
7-Hydroxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (750 mg, 2.7 mmol) was suspended in methylene chloride (40 ml) at 5° C. and 4-(3-hydroxypropyl)morpholine (490 mg, 3.4 mmol) and triphenylphosphine (890 mg, 3.4 mmol) were added. The mixture was stirred for 5 minutes and diethyl azodicarboxylate (590 mg, 3.4 mmol) was added over 5 minutes at 5° C. The reaction mixture was stirred at 5° C. for 30 minutes then at ambient temperature for 1 hour. The solution was then purified directly by column flash chromatography eluting with methylene chloride, and then ethyl acetate, acetonitrile/ethyl acetate (20/80), and acetonitrile/ethyl acetate/ammonia (50/50/0.5). The purified product was triturated with ether/isohexane and collected by filtration to give 7-(3-morpholinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (745 mg, 68%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.Br>C(O)(=O)C.CCOCC>[F:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (2.9 g, 6.9 mmol, 1.0 eq) and 33% HBr in acetic acid (30 ml). The mixture was stirred at room temperature for 3 hours and diluted with ether to give a pale white solid. The solid was filtered, washed with ether and dried to yield 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol as a pale white solid (2.74 g, 97.5% yield). 1H NMR (400 MHz, CDCl3): 11.89 (bs, 1H), 8.87 (d, 1H), 8.57 (d, 1H), 8.30 (d, 1H), 7.89 (m, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 4.03 (s, 3H); MS (EI) for C16H11FN2O5: 421 (M+H+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH:23]=1)[CH2:21][OH:22]>C(OCC)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH:23]=1)[CH:21]=[O:22]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C=O)c1
Yield: 83 %

Procedure:
Pyridinium chlorochromate (25.0 g, 116 mmol) was added to methylene chloride (65 ml) while stirring, and then thereto was added 5-methyl-2-nitrobenzyl alcohol (12.9 g, 77.3 mmol). The mixture was stirred at room temperature for 15 hours, and diethyl ether (155 ml) was added. The ether layer was removed by decantation. Diethyl ether (30 ml) was added to the residue, and the ether layer was removed by decantation (3 times). The ether layers were combined, and passed through 15.5 g of silica gel. The obtained solution was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (8:1), whereby 10.6 g of 5-methyl-2-nitrobenzaldehyde was obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.IC.O>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was allowed to stir at 0° C. for 15 min, then slowly allowed to warm to rt and to stir overnight. After 12 h, the reaction mixture was poured into 200 mL of H2O and extracted with EtOAc (2×100 mL). The organic solutions were combined, washed with H2O (2×100 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-iodo-2-nitrobenzoate (2.3 g, 96%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccoc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccoc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with furan-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(furan-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[SH:32]>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[S:32][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[C:15]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1F
Product: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1Sc1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in Example 11, Step A, the title compound was prepared using 2-fluoro-4-[5-(2-morpholin-4-yl-ethyl)-imidazol-1-ylmethyl]-benzonitrile (0.15 g, 0.477 mmol) and 2,4-dichlorothiophenol (0.086 g, 0.477 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[C:4]([F:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])O1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[F:17][C:4]1[CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Reactant: Fc1cc(Br)ccc1-c1cnc2[nH]ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc3[nH]ccc3n2)c(F)c1
Temperature: 110 °C
Yield: 69.2 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (50 mg, 0.17 mmol), N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methane-sulfonamide (61 mg, 0.21 mmol) and Pd(dppf)Cl2.CH2Cl2 (6.7 mg, 0.009 mmol) in a microwave vial were added acetonitrile (2.0 mL) and sat. NaHCO3 (2.0 mL). The vial was sparged with nitrogen for 5 min then heated at 110° Celsius for 90 min via microwave irradiation. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL) and brine (25 mL), dried (Na2SO4) and concentrated to dryness. The crude product was purified by HPLC giving the title compound (45 mg, 69%). MS (ESI): mass calcd. for C19H15FN4O2S, 382.09; m/z found, 383.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.78 (d, J=2.7, 1H), 8.20-8.12 (m, 1H), 7.71-7.64 (m, 2H), 7.48-7.39 (m, 1H), 7.37-7.31 (m, 2H), 7.28-7.21 (m, 2H), 6.91 (s, 1H), 6.81-6.75 (m, 1H), 2.93 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[C:13]([F:21])([F:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:15]2)[C:13]([F:21])([F:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 106.1 %

Procedure:
An optically-active compound of 3,3-difluoro-1,6-diaza-spiro[3.5]nonane-1-carboxylic acid benzyl ester 1 hydrochloride (11.2 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.2 g), potassium carbonate (18.7 g) and water (104 ml), and the mixture was stirred for 16.5 hours with refluxing. The mixture was cooled to room temperature, and thereto were added ethyl acetate and water. The mixture was filtered, and the filtrate was separated and the resulting organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=3/1). The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=2/1) again to give the titled compound (12.0 g).
Reaction SMILES: FC(F)(F)C(O)=O.CC1(C)[N:13](C(O)=O)[C@@H:12](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:11][O:10]1.[OH-].[Na+]>O.C(#N)C>[NH2:13][C@@H:12](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:11][OH:10]
Reactant: CC1(C)OC[C@H](/C=C/c2ccc([N+](=O)[O-])cc2)N1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N[C@@H](/C=C/c1ccc([N+](=O)[O-])cc1)CO
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of trifluoroacetic acid (4.9 ml) in water (24 ml) was added (S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylic acid tent-butyl ester (Example 14(a)) (5.0 g) in acetonitrile (4.0 ml). After stirring at 80° C. for 4 hours, the reaction mixture was cooled to room temperature and the solution basified to pH>11 by dropwise addition of a 1N solution of sodium hydroxide The mixture was extracted three times with ethyl acetate, the combined organic layers were dried (MgSO4) and concentrated in vacuo to yield (E)-(S)-2-Amino-4-(4-nitro-phenyl)-but-3-en-1-ol as a brown oil (2.5 g). 1H-NMR (300 MHz, CDCl3, δ); 8.23-8.11 (m, 2H), 8.54-8.47 (m, 2H), 7.67 (d, J=16 Hz, 1H), 6.7 (dd, J=16 and 8 Hz, 1H). 3.78-3.69 (m, 2H), 3.58-3.42 (m, 1H).