Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:14][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3C#N)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzonitrile (0.22 g, 1 mmol) in isopropanol (8 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (MeOD) δ: 1.40 (6H, s), 2.30-2.58 (8H, m), 3.00-3.15 (4H, m), 5.20 (1H, br s), 6.18 (1H, t), 6.70 (1H, dd), 7.18-7.84 (7H, m), 8.50 (1H, dd). ESI-MS m/z: 515 (M+1), UV retention time: 1.75 min.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[OH:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC(O)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-Azido-1-(3-bromo-phenyl)-ethanol (3.38 g, 13.8 mmol) in THF (40 mL) was added water (2.48 ml, 138 mmol) and triphenylphosphine (7.26 g, 27.7 mmol). The mixture stirred for 2 hours at 50° C. and was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organics were washed with 1M HCl (2×) and the aqueous washes were combined and neutralized with 1N sodium hydroxide. The aqueous mixture was extracted with ethyl acetate and the organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound was isolated as a yellow oil (2.53 g, 85%). 1H NMR (300 MHz, CDCl3): 7.55 (s, 1H), 7.41 (d, 1H), 7.31-7.20 (m, 2H), 4.62 (m, 1H), 3.02 (d, 1H), 2.79 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[C:15]([OH:18])=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH2:1]([O:8][C:9]1[C:14]2[C:15]([O:18][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1noc2cccc(OCc3ccccc3)c12
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCc4ccccc4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 8 using 4-(benzyloxy)-1,2-benzisoxazol-3-ol (EXAMPLE 7, Step 1) and tert-butyl 4-(hydroxymethyl)-piperidine-1-carboxylate instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)-piperidine-1-carboxylate.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[C:4]2[C@H:14]3[CH2:15][C@H:13]3[C:12]([F:17])([F:16])[C:5]=2[N:6]([CH2:8][C:9](O)=[O:10])[N:7]=1.[NH2:19][C@H:20]([C:30]1[N:35]=[C:34]([N:36]2[CH2:39][C:38]([CH3:41])([OH:40])[CH2:37]2)[CH:33]=[CH:32][C:31]=1[Br:42])[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:42][C:31]1[C:30]([C@@H:20]([NH:19][C:9](=[O:10])[CH2:8][N:6]2[C:5]3[C:12]([F:17])([F:16])[C@@H:13]4[CH2:15][C@@H:14]4[C:4]=3[C:3]([CH:2]([F:18])[F:1])=[N:7]2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[N:35][C:34]([N:36]2[CH2:39][C:38]([OH:40])([CH3:41])[CH2:37]2)=[CH:33][CH:32]=1
Reactant: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: CC1(O)CN(c2ccc(Br)c([C@@H](N)Cc3cc(F)cc(F)c3)n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)n2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (33 mg, 0.13 mmol), (S)-1-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-2-yl)-3-methylazetidin-3-ol (50 mg, 0.13 mmol) and HATU (57 mg, 0.15 mmol) were dissolved in 1 mL of DMF and cooled to 0° C. To it was dropwise added N,N-diisopropylethylamine (0.07 mL, 0.38 mmol). The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (saturated aqueous) and brine. After dried over MgSO4, it was filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford the title product. MS (m/z): 644.33[M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]([O:16]CC)=[O:15])=[CH:8][C:4]=2[CH:5]=[N:6][N:7]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1B(O)O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:2]1[C:3]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]([OH:16])=[O:15])=[CH:8][C:4]=2[CH:5]=[N:6][N:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCOC(=O)c1cc2cnnc(Cl)c2n(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)c(C(=O)O)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 100 °C

Procedure:
To a suspension of ethyl 8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate (6) (1.40 g, 5.23 mmol) in 3:1 1,4-dioxane: 2 M aq Na2CO3 (16 mL) was added 2,4-difluorophenylboronic acid (1.03 g, 6.54 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.484 g, 0.418 mmol). The reaction mixture was heated in a microwave at 100° C. for 75 min, then more Na2CO3 solid (100 mg) was added and the reaction mixture was heated in the microwave at 100° C. for an additional 2 h. The mixture was diluted with water and washed with CH2Cl2. The aqueous layer was then acidified with 5 N HCl to pH ˜2 and extracted with CHCl3/iPrOH (4:1). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid as a brown solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].CN(C=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH3:23][O:22][C:20](=[O:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCCC1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.65 g (32.5 mmol) of potassium tert-butoxide in 65 ml of abs. DMF was cooled to 0° C., and a solution of 5.0 g (27.08 mmol) of methyl 4-chlorophenylacetate in about 2 ml of abs. DMF was added dropwise. The mixture was stirred at 0° C. for 30 min, and 4.84 g (32.5 mmol) of cyclopentyl bromide were then slowly added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then added to water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 6.28 g of the target compound (91.8% of theory).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([CH:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[N:29]=5)[N:26]=4)[CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3]N=1.N[C:35]1C=C(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)C=CC=1.C1(S(Cl)(=O)=O)C2C(=CC=CC=2)C=CC=1>>[C:6]1([S:11]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[N:29]=4)[N:26]=3)[CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:13])[C:5]2[C:10](=[CH:1][CH:35]=[CH:3][CH:4]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5cnccc45)c3)ccc2n1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(N)c3)ccc2n1
Agent: O=S(=O)(Cl)c1cccc2ccccc12
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5ccccc45)c3)ccc2n1

Procedure:
Following the procedure for compound N-(6-(3-(isoquinoline-5-sulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 6), N-(6-(3-aminophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 5) (0.032 g, 0.12 mmol) was reacted with 1-naphthalenesulfonyl chloride (0.034 g, 0.15 mmol, Aldrich, St. Louis, Mo.) to afford the title compound as a white solid. MS (ESI positive ion) m/z: 458 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.92 (s, 1H), 10.91 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.4 Hz, 1H), 8.21-8.24 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 8.02 (d, J=9.4 Hz, 1H), 7.74-7.78 (m, 1H), 7.62-7.70 (m, 3H), 7.58 (d, J=7.8 Hz, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8.0 Hz, 1.6 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:8][C:7]1[C:2]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(Oc2nccnc2Cl)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and tert-butyl (3-hydroxycyclobutyl)carbamate (see PREPARATION 4B; 3.65 g, 20 mmol) in DMSO (50 mL) was added Cs2CO3 (13.2 g, 40 mmol), and then the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water and filtered. The filtrate cake was washed with water, and dried to give tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2 mmol, 76%). ESI-MS (M+1): 300 calc. for C13H18ClN3O3 299.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23]>>[C:25]([N:24]([CH2:22][CH3:23])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCNC(C)(C)C
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Product: CCN(c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(C)(C)C
Temperature: 120 °C
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 79 mg, 0.280 mmol) and N-ethyl-2-methylpropan-2-amine (142 mg, 1.399 mmol, TCI International, Portland, Oreg.), heating at 120° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10100% ACN/water with 0.1% TFA) provided 2-(3-(tert-butyl(ethyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=6.94 Hz, 3H) 1.60 (s, 9H) 2.85 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 3.80 (q, J=6.91 Hz, 2H) 6.94 (br. s., 1H) 7.03 (d, J=2.15 Hz, 1H) 7.41 (t, J=7.73 Hz, 1H) 7.69 (d, J=8.22 Hz, 1H) 7.87 (d, J=7.43 Hz, 1H) 8.71 (s, 1H) 11.69 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.1 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[O:17][CH3:18].[N+:19]([O-])([OH:21])=[O:20]>ClCCl.C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:19]([O-:21])=[O:20])[C:7]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(OCCCCl)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCCCl)c(OC)c1[N+](=O)[O-]
Yield: 82 %

Procedure:
WO 02/36587 describes a process for preparing a 5-alkoxy-4-halogenoalkoxy-2-nitrobenzoic acid compound from a 3-alkoxy-4-hydroxybenzoic acid compound. For example, ethyl vanillate (i.e., ethyl 4-hydroxy-3-methoxybenzoate) is reacted with 3-bromo-1-chloropropane in an aqueous potassium carbonate solution in the presence of N-butyl-ammonium bromide to produce ethyl 4-(3-chloropropoxy)-3-methoxybenzoate, and the ethyl 4-(3-chloropropoxy)-3-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give ethyl 4-chloropropoxy-3-methoxy-2-nitrobenzoate in 82% yield (based on the amount of ethyl vanillate).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg]CCCC)CCC.C([Li])CCC.[C:28]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>CCCCCCC.C1COCC1>[OH:33][C:28]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCCC1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(O)C1(c2ccc(C3(O)CCCC3)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (600.0 mg, 0.002489 mol) in tetrahydrofuran (20 mL, 0.2 mol) was cooled below −20 Celsius under N2 atmosphere, and 1.0 M of dibutylmagnesium in heptane (1.3 mL) was slowly added to the solution while maintaining the temperature below −20 Celsius. Then n-butyllithium (2.5 M in hexane, 1.1 mL) was slowly added to the slurry while maintaining the temperature below −20 Celsius with effective stirring. After the mixture was stirred at −20 Celsius for 1 hour, a solution of cyclopentanone (0.264 mL, 0.00299 mol) in THF (20.0 mL) was added to the mixture. Then after stirring at −20 Celsius for 1 hour, the reaction was quenched with ammonium chloride and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, then dried over Na2SO4, and then filtered. The filtrate was concentrated. The residue was flash chromatographed on silica gel column with 30% ethyl acetate in hexanes to afford the desired compound. MS (ESI): 229.1 (M-OH−), 269.1 (M+Na+).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10](Cl)[S:9][N:8]=2)=[CH:3][CH:2]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.O=O>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:10]2[S:9][N:8]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:13])=[CH:2][CH:3]=3)[N:11]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nsc(Cl)n2)cc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nsc(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A mixture of 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole (0.50 g, 2.37 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride catalyst (1.41 g, 2.61 mmol) in anhydrous THF (20 ml) is cooled in an ice-water bath. To this mixture is added slowly 4-fluorophenyl-magnesium bromide (1.0M in THF, 2.5 ml, 2.49 mmol) with exclusion of both moisture and oxygen. The mixture is allowed to warm to room temperature and stirred for 18 hours under N2. The mixture is filtered through celite and concentrated. The residue is taken up in CHCl3 (50 ml) and washed with brine (50 ml×2). The organic layer is dried over magnesium sulfate and concentrated. The residue is purified on a silica gel column, eluting with 3:7 CHCO3:hexanes to yield 5-(4′-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.20 g, 31%). 1H NMR (CDCl3): δ 2.43 (s, 3H), 7.21-7.32 (m, 4H), 8.06 (m, 2H), 8.24 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1

Procedure:
The solution of 1-(4-methylphenyl)-2-phenylethanone (2-1) (Renault, O; Dallemagne, P.; and Rault, S. Org. Prep. Proced. Int. 1999, 31, 324) (3.29 g, 15.65 mmol) and N,N-dimethylformamide dimethylacetal (4.66 g, 39.12 mmol) in DMF (15 mL) was stirred at 110° C. for 1 h. The mixture was concentrated in vacuo to give 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (2-2. LRMS m/z (M+H) Calcd: 266.4, found: 266.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].C(Cl)(Cl)[Cl:14]>>[Cl:14][C:7](=[N:8][OH:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Reactant: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Yield: 93.7 %

Procedure:
32.9 g (0.2 mol) of 3-nitrobenzaldoxime was suspended in 150 g of chloroform and chlorine gas was bubbled into the suspension while maintaining the reaction mixture at a temperature of from 5° to 10°C. 3-Nitrobenzaldoxime went into solution showing a green color upon reaction with chlorine to give a reaction mixture having a deep green color. The reaction mixture turned a pale yellowish-brown upon standing; chloroform was then removed from the reaction mixture under reduced pressure to give 37.6 g of pale yellow crystals having a melting point of 98°-101°C. Yield, 94%.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:30]([C:29]3[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester (5.2 g, 0.017 mol) and 4-(trifluormethoxy)aniline (4.57 ml, 0.034 mol) in toluene (200 ml) under an argon atmosphere at room temperature, was added dimethylaluminium chloride (0.9M solution in heptane, 37 ml, 0.034 mol) and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and quenched was sat. Na2SO4(aq) solution and the mixture was filtered through Celite® and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (1:3 AcOEt/heptane) to give 8-benzyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one as a white solid. MS (ESI): 405.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2].[CH2:34]([NH:36][CH3:37])[CH3:35]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:36]([CH2:34][CH3:35])[CH3:37])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[F:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Reactant: CCNC
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N(C)CC)nc2c(F)cc(Cl)cc2c1Cc1ccccc1Cl
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A solution of 6-chloro-4-(2-chloro-benzyl)-8-fluoro-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (108 mg, 0.205 mmol, Eq: 1.00) and ethyl-methyl-amine (12.7 mg, 18.5 μl, 0.215 mmol, Eq: 1.05) in DMSO (1.5 ml) was heated to 40° C. for 65 h. Additional ethyl-methyl-amine (60.6 mg, 88.1 μl, 1.02 mmol, Eq: 5) was added and the solution was heated to 80° C. for 1.5 h. The solution was cooled to RT, diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 96.5:3.5) to afford the title compound as yellow solid (48 mg). MS (ESI): 435.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29]>CCOC(C)=O>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:4]3[C:1]([CH3:2])=[N:32][N:31]([CH:28]([CH3:30])[CH3:29])[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: CC(C)NN
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nn(C(C)C)c2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 58 using 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methyl-pyridin-2(1H)-one (Step 58.1) and isopropylhydrazine hydrochloride. tR: 4.69 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 431/433 [M+H]+ (LC-MS 2); Rf=0.55 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.57 (m, 6H) 1.93 (s, 3H) 3.44 (s, 3H) 4.67-4.79 (m, 1H) 6.11 (s, 1H) 7.28 (d, J=8.2 Hz, 2H) 7.40 (d, J=8.2 Hz, 2H) 7.91 (d, J=2.0 Hz, 1H) 7.95 (d, J=2.4 Hz, 1H).
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C(#N)C>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[C:19]([C:18]2[CH:21]=[CH:22][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:16][CH:17]=2)[NH:20][C:9]=1[CH3:11])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)[nH]c1C
Temperature: 0 °C
Yield: 71.8 %

Procedure:
To a solution of 7.9 g of ethyl 2-oximinoacetoacetate in acetonitrile (100 ml) was added 10.5 g of 4-(trifluoromethoxy)benzylamine (as R4—CH2—NH2). The reaction mixture was then refluxed for 17 hours under argon atmosphere. After such time the reaction mixture was cooled down to 0° C., the solid was filtered off, washed with acetonitrile, and dried in vacuo to yield 11.2 g of a light yellow powder, MS (ISP) 315 (M+H)+.