Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=[CH2:29])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=[CH:29][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1C(=O)NN=C2COc3ccc(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step D, 0.30 g, 1.013 mmol), 3-methylene-azetidine-1-carboxylic acid tert-butyl ester (0.343 g, 2.026 mmol), Pd(OAc)2 (0.023 g, 0.101 mmol), tri-O-tolylphosphine (0.0617 g, 0.203 mmol) and triethylamine (0.308 mg, 3.04 mmol) in CH3CN (10 mL) was heated at 110° C. for 14 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene)-azetidine-1-carboxylic acid tert-butyl ester as yellow solid (0.201 g, 52%), which was used directly in the next step. LC/MS (Table 1, Method 2) Rt=1.264 min; MS m/z: 385 [M+H]+.
Reaction SMILES: [C:1]([C:11]1[S:27][C:14]2[C:15]3[S:23][C:22]4[C:21]5[S:24][CH:25]=[CH:26][C:20]=5[S:19][C:18]=4[C:16]=3[S:17][C:13]=2[C:12]=1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pt].C(OCC)(=O)C>[CH2:1]([C:11]1[S:27][C:14]2[C:15]3[S:23][C:22]4[C:21]5[S:24][CH:25]=[CH:26][C:20]=5[S:19][C:18]=4[C:16]=3[S:17][C:13]=2[C:12]=1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Reaction time: 24 h

Procedure:
2-dec-1-ynyl-3-decanyldithieno[2,3-d:2′,3′-d′]thieno[3,2-b:4,5-b′]dithiophene (107) (2.2 g, 4.15 mmol) was dissolved into ethyl acetate (30 mL). To this solution, 5% Pt/C (0.5 g) was added. The mixture was stirred under a H2 atmosphere (90 psi) for 24 hours. The solution was then filtered. After removal of the ethyl acetate, the residue was purified by chromatography on silica gel eluted with hexane to produce the target compound (2.00, 90.5%). Mp. 50.9-52.5° C. 1HNMR: solvent, CD2Cl2 δ 7.41 (d, 1H), 7.33 (d, 1H), 2.83 (t, 2H), 2.50 (t, 2H), 1.73-1.26 (m, 32H), 0.87 (m, 6H). 13CNMR: 140.85, 140.40, 139.93, 133.38, 133.14, 132.22, 129.69, 121.17, 120.09, 98.92, 32.29, 32.25, 29.99, 29.94, 29.72, 29.63, 29.52, 29.33, 29.18, 29.06, 28.94, 23.05, 14.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[CH3:9].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:17])[F:18])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([N:32]1[C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]2[C:28]1=[O:38])[CH3:9]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
In a solution of 0.88 g of 3-[3-chloro-4-(1-chloroethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 5 mL of N,N-dimethylformamide, 0.36 g of potassium phthalimide was added, and stirred at 100° C. for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and diluted with 20 mL of ethyl acetate, washed with water (10 mL×3), and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:10 to 1:3) to obtain 0.45 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[CH2:23]([O:27]C1N=C(C(O)=O)C=CC=1)[CH2:24][CH2:25][CH3:26].S(Cl)(Cl)=O>C(O)CCC>[CH2:23]([O:27][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: CCCCOc1cccc(C(=O)O)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOc1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
To methyl 6-chloro-pyridine-2-carboxylate (2.58 g, 15.0 mmol, obtained from Example 17(a)) was added 1-butanol (35 mL) followed by sodium bis(trimethylsilyl)amide (5.51 g, 30.1 mmol). The suspension was warmed to 130° C. for 24 h after which more sodium bis(trimethylsilyl)amide (5.51 g, 30.1 mmol) was added. After another 24 h at reflux, the solution was cooled to r.t. and was poured into 200 mL 1N HCl in an ice bath. The aqueous solution was extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo resulting in 3.79 g of crude 6-butoxy-pyridine-2-carboxylic acid. To the crude 6-butoxy-pyridine-2-carboxylic acid was added thionyl chloride (100 mL) and after 1 h the resulting solution was concentrated in vacuo. To the residue was slowly added anhydrous methanol (100 mL) and after stirring o.n., the solvents were removed in vacuo. The resulting 3.73 g of crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 8:1) resulting in 2.46 g of the title compound as a colourless oil (78% yield, 11.7 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][I:19].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[I-:19].[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][P+:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCI
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Temperature: 25 °C

Procedure:
To a mixture of EXAMPLE 111A (0.136 g) in CH3CN (5 mL) was added triphenylphosphine (157 mg). The mixture was refluxed for 48 hours, cooled to room temperature, washed with hexanes and concentrated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a solution of 3.1 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride in 100 ml of acetonitrile, 1.9 g of 2-amino-5-chloro-3-methylbenzoic acid was added. The mixture was stirred at room temperature for 10 minutes and then, 1.0 g of triethylamine was added thereto. The mixture was stirred at room temperature for 20 minutes and then, 2.0 g of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 1.2 g of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were poured into the residue to separate layers. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressured. The resulting residue was subjected to silica gel column chromatography to obtain 4.2 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17]C([O-])(C)C.[K+].CI>C1COCC1.O>[CH3:17][N:4]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](=[O:16])[O:2][CH3:1]
Reactant: COC(=O)NCCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COC(=O)N(C)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl[2-(4-nitrophenyl)ethyl]carbamate (224 mg, 1 mmol) in THF (2 mL) was added KOtBu (201 mg, 1.8 mmol) and MeI (256 mg, 1.8 mmol) sequentially. The reaction mixture was stirred for 12 hours at room temperature. The reaction was diluted with water (5 mL), extracted with EtOAc (2×15 mL), washed with water (5 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (60% ethyl acetate/hexane) afforded the title compound as a semi solid (160 mg, 67.2%). MS (ES+): 239 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].[ClH:13].[CH3:14][NH:15][CH3:16].[CH3:17]C(=O)CC>>[ClH:13].[CH3:14][N:15]([CH2:17][CH:10]1[CH2:11][CH:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:7][CH2:8][C:9]1=[O:12])[CH3:16]
Reactant: CC(C)COC1CCC(=O)CC1
Reactant: CNC
Reactant: CCC(C)=O
Agent: Cl
Product: CC(C)COC1CCC(=O)C(CN(C)C)C1
Yield: 53 %

Procedure:
Compound (21) was reacted with dimethylamine hydrochloride corresponding to the conditions described in Example 10, step 3. The compound of formula (22) was obtained from 2-butanone in a yield of 53% theoretical.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50](O)=[O:51]>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]#[N:15])([NH:16][C:50]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([CH3:44])[CH:53]=2)=[O:51])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.485 g, 2.15 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (11 mL) and N-ethyl diisopropylamine (0.44 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.047 g, 2.37 mmol, 1.1 equiv; BOP reagent) 5-methyl-nicotinic acid (0.295 g, 2.15 mmol, 1.0 equiv) and the reaction mixture stirred at 40° C. during a weekend. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.48 g (65%) of the title compound as off-white foam. MS (ISP): 345.3 [M+H]+
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Br[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:11]([O:10][CH:9]([O:13][CH2:14][CH3:15])[CH2:8][O:6][CH:3]([CH3:5])[CH3:4])[CH3:12]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(COC(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (3.35 g, 84 mmol) was added to isopropanol (5.38 mL, 69.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min followed by the addition of 2-bromo-1,1-diethoxyethane (7.89 mL, 52.4 mmol). The tube was sealed, heated to 120° C. and stirred overnight. The sealed tube was cooled to room temperature and the contents were dissolved in DCM and washed with water twice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give 2-(2,2-diethoxy-ethoxy)-propane, which was hydrolyzed according to the method described in example 29 to give crude isopropoxy-acetaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[C:28]1([NH:34][C:35]([NH:1][CH2:2][CH2:3][C:4]([C:6]2[CH:20]=[CH:19][C:9]3[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=3[CH:7]=2)=[O:5])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)Nc3ccccc3)cc2s1
Reaction time: 0.08 h
Yield: 21.9 %

Procedure:
A solution of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea (0.033 g, 0.10 mmol) in 1 mL anhydrous DMF was treated with triethylamine (0.028 mL, 0.20 mmol, 2.0 eq) at room temperature. It was stirred for about 5 min, followed by the addition of phenyl isocyanate (0.013 mL, 0.12 mmol, 1.2 eq). It was stirred for about 2.5 hours, quenched with MeOH, filtered, concentrated, and purified by HPLC to give the desired compound 0.009 g (22%). LC/MS 412.2 (M+1); LC retention time 2.80 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31]([O:33][CH3:34])=[O:32])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:35].[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16]([C:31]([O:33][CH3:34])=[O:32])=[N:17]2)=[CH:23][C:24]=1[F:30])#[N:29]
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (142 mg, 0.30 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.375 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under reduced pressure for 2 hours, 105 mg of methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate HCl salt was obtained as an off-white solid. MS (ESI) 373 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]([N:8]([CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[CH2:27]([NH:34][CH:35]=[CH:36][C:37](=[O:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:37]([C:36]1[CH:18]([CH2:17][CH2:16][CH2:15][N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:19]=[CH:20][N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)C=CNCc1ccccc1
Reactant: COc1ccc(C(=O)N(CCC/C=C/C=O)c2ccccc2)cc1OC
Product: COc1ccc(C(=O)N(CCCC2C=CN(Cc3ccccc3)C=C2C(C)=O)c2ccccc2)cc1OC

Procedure:
The title compound 36 is prepared according to the procedure reported in step D of Example 8 with aldehyde 38 (706 mg, 2 mmol) and enamine 30 (350 mg, 2 mmol) as reactants. (Yield 360 mg, 35%).
Reaction SMILES: CC[O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5].[OH-].[Na+]>O.CO>[NH:7]1[C:8]2[C:13](=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
Solution of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester# (20.0 g, 85.75 mmole) and NaOH (100 mmole) in a mixture of water/MeOH (1/1) (200 ml) was stirred at 50° C. for 4 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (200 ml) and acidified with 1M HCl up to pH=3. The precipitates were collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give indole-2,5-dicarboxylic acid 1 (10.38 g, 59%) of compound 1 as white crystals. MS: 203.7 (M-2H); 204.7 (M−H). 1-NMR (DMSO-d6): 8.32 (m, 1H, H-4, indole); 7.80 (m, 1H, H-6, indole); 7.45 (d, 1H, H-7, indole); 7.22 (s, 1H, H-3, indole).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Temperature: 25 °C
Yield: 148.3 %

Procedure:
Heat a mixture of (3R,4R)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.02 mol, 6.0 g), 5-bromo-2-fluoronitrobenzene (0.03 mol, 6.71 g) and triethyl amine (0.058 mol, 5.88 mL) in ethyl acetate (180 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (12.35 g, crude). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.50-1.51 (m, 1H), 2.08-2.12 (m, 1H), 2.93 (dd, 1H), 3.01 (br s, 1H), 3.55-3.61 (m, 1H), 3.62-3.68 (m, 1H), 3.68 (br s, 1H), 4.13-4.18 (m, 1H), 6.97 (d, 1H), 7.48 (dd, 1H), 8.08 (d, 1H), 8.30 (d, 1H). ES-MS m/z 316 [M−Boc]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])[N:7]([CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:32](F)(F)S(OC)(=O)=O.[NH4+].[OH-]>C1(C)C=CC=CC=1.O.CC(C)=O>[C:1]([C:5]1[N:6]([CH3:32])[N:7]([CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])/[C:8](=[N:10]/[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=2[F:22])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(CCCC(F)(F)F)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1CCCC(F)(F)F
Temperature: 100 °C
Reaction time: 20 h
Yield: 74.4 %

Procedure:
To a solution of Example 135C (1.7 g, 3.9 mmol) in toluene (15 mL) was added methyl trifluoromethanesulfonate (0.64 mL, 5.8 mmol). The mixture was warmed to 100° C. and stirred for 20 hours, cooled to ambient temperature and diluted with water (20 mL) and acetone (50 mL). This solution was allowed to stir for 30 minutes then concentrated NH4OH (10 mL) was added. The mixture was stirred for 30 minutes then partially concentrated under reduced pressure. The mixture was diluted with EtOAc (30 mL) and brine (10 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 80% hexanes/EtOAc to 100% EtOAc to 10% MeOH in EtOAc) afforded the title compound (1.3 g, 2.9 mmol, 74% yield). MS (ESI−) m/z 454 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Product: CCOC(=O)c1cc2cc(OCCCCCBr)ccc2o1
Yield: 73 %

Procedure:
Starting with 2.41 g (11.69 mmol) of 5-hydroxy-2-benzofurancarboxylic acid ethyl ester, and 8.06 g (35.06 mmol) of 1,5-dibromopentane, the title compound (3.03 g; 73%) was obtained as a white solid, mp 31° C., using the procedure of example 21.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([CH2:35][C:36](OC)=[O:37])[CH2:31]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][C@H:32]5[CH2:33][CH2:34][C@H:30]([O:29][CH3:28])[CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)C1

Procedure:
The title compound, white solid (117 mg, 99%), MS (ISP) m/z=471.6 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 2-((1S,3S)-3-methoxy-cyclopentyl)-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]1[O:14][CH:5]21.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[C@@H:6]([OH:14])[C@@H:5]2[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]1=[O:15]
Reactant: CC1(C)Oc2ccc(Cl)cc2C2OC21
Reactant: Oc1ccccn1
Product: CC1(C)Oc2ccc(Cl)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
Following the procedure of Example 3, 6-chloro-2,2-dimethyl-3,4-epoxychromane is prepared and reacted with 2-hydroxypyridine to give the expected product. Melting point: 250° C.