Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Example 148 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25]C(=O)C)[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[N:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25][S:34]([CH:31]5[CH2:33][CH2:32]5)(=[O:36])=[O:35])[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[N:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-n3cccn3)c2)cn1

Procedure:
The compound was prepared from the compound of Example 114 using the procedures of Example 115 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, CD3OD): δ 8.54 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.93 (d, 1H), 7.88 (s, 1H), 7.82-7.8 (m, 3H), 7.72 (d, 1H), 7.65-7.62 (m, 1H), 7.53-7.52 (m, 1H), 6.6-6.59 (m, 1H), 3.95 (s, 3H), 2.81-2.78 (m, 1H), 1.18-1.15 (m, 2H), 1.09-1.04 (m, 2H); LC-MS (ESI): Calculated mass: 459.52; Observed mass: 460.1 [M+H]+ (rt: 0.58 min).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:18]=[C:17]([C:19](O)([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=3[CH3:23])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25].[N-:28]=[N+:29]=[N-:30].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[N:28]([C:19]([C:17]1[CH:16]=[CH:15][C:14]([CH3:23])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:24])[C:5](=[O:25])[N:4]([CH2:3][C:2]([CH3:1])([CH3:26])[CH3:27])[C:12]3=[CH:11][CH:10]=2)[CH:18]=1)([CH3:20])[CH3:21])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(C)(C)O)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)N=[N+]=[N-])cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 14-2 (1.2 g, 3.3 mmol) and sodium azide (0.42 g, 6.5 mmol) in DCM (8 mL) at −78 C was added a solution of trifluoroacetic acid (1.0 mL, 13 mmol) in DCM (0.25 mL). The reaction mixture was allowed to slowly warm to room temperature over 15 hours. The reaction was diluted in EtOAc and washed with water, brine, dried over sodium sulfate, filtered and concentrated to give product. HRMS (M+H)+: observed=393.2389, calculated=393.2397.
Reaction SMILES: O[CH:2]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CS(Cl)(=O)=O.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:34]1([CH:2]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: CCCCC(O)CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: c1c[nH]cn1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCC(CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC)n1ccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
Diethyl 2-(12-hydroxyhexadecyl)malonate (1.75 g, 4.369 mmol), TEA (0.79 ml, 5.679 mmol) and DMAP (53 mg, 0.437 mmol) were dissolved in dry DCM (20 ml), cooled to 0° C., then methane sulfonyl chloride (0.36 ml, 4.587 mmol) was slowly added. The ice bath was removed, and stirring continued for another 2 h at room temperature. The reaction mixture was diluted with DCM (75 ml), washed with water (50 ml), 0.5 N HCl (10 ml) and brine solution (20 ml), dried on dry MgSO4 and concentrated. The crude compound was mixed with imidazole (595 mg, 8.737 mmol) and stirred at 75° C. for 16 h. The crude compound was purified by silica gel column (2% MeOH in DCM) to give diethyl 2-(12-(1H-imidazol-1-yl)hexadecyl)malonate (640 mg, 32.5%) as a light brown coloured liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[CH:27][CH:26]=2)[CH2:7]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 47.8 %

Procedure:
Example 39 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 9 (0.055 g) and 4-(methylsulphonyl)phenylacetic acid (0.050 g) to give the title compound (0.045 g).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[C:8](#[N:11])[CH:9]=[CH2:10].[OH-].C[N+](C)(C)CC1C=CC=CC=1.C>C(O)C.CO>[O:7]=[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][N:2]1[CH2:10][CH2:9][C:8]#[N:11]
Reactant: O=c1cccn[nH]1
Reactant: C=CC#N
Agent: C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: N#CCCn1ncccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a stirred solution of 3.84 g (0.04 mole) of 3(2H)-pyridazinone, 2.33 g (0.044 mole) of acrylonitrile in 50 ml of ethanol, 1 ml of Triton-B (trimethyl benzylammonium hydroxide, 40% methanol solution) was added dropwise. The mixture was stirred for 2 hours at 60° C. and then evaporated to dryness in a vacuum on a steam bath, giving a dark orange oil. The oil was dissolved in ethanol, shaken with Norit and filtered. The filtrate was distilled. Recrystallization of the residue from ethanol and isopropyl ether gave 4.7 g (79% yield) of 3-(3-oxo-2-pyridazinyl)-propionitrile in the form of pale yellow crystals, m.p. 75°-76° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.N12CCCN=C1CCCCC2>O1CCOCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:22]4[O:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Clc1nc2ccccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3nc4ccccc4o3)CC2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To the 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.080 g, 0.290 mmol) in dioxane (7 mL) was added 2-chlorobenzooxazole (0.053 g, 0.34 mmol) followed by the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (0.132 mL, 0.87 mmol) and tetra-n-butylammonium iodide (3 mg). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate, then washed with citric acid, sodium bicarbonate and brine solution. The organic layer was separated, and dried over anhydrous Na2SO4, and evaporated. The residue was purified by recrystallization from n-hexane to yield the title compound as a white powder in 44% yield (0.050 g). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9.5 Hz, 1H), 7.99 (t, J=5.3 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.19 (m, 1H), 7.05 (m, 2H), 3.92 (m, 8H), 3.55 (m, 2H), 1.48 (m, 2H), 0.79 (m, 1H), 0.46 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 393 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].N1CC[CH:24]([C:27]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=CC=C(Cl)C=3)[CH:30]=2)=[O:28])[CH2:23]C1.BrCCC(C1C=CC=CC=1)O.ClCCCC(C1C=CC(F)=CC=1)=O>>[C:29]1([CH:27]([OH:28])[CH2:24][CH2:23][N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][C:5]3[C:4]([O:3][CH2:1][CH3:2])=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=3)[CH2:16][CH2:17]2)[CH:38]=[CH:37][CH:36]=[CH:31][CH:30]=1
Reactant: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Reactant: CCOc1cc2ccccc2cc1CC1CCNCC1
Agent: O=C(CCCCl)c1ccc(F)cc1
Agent: OC(CCBr)c1ccccc1
Product: CCOc1cc2ccccc2cc1CC1CCN(CCC(O)c2ccccc2)CC1

Procedure:
When in the procedure of Example 25, 4-[(3-ethoxy-2-naphthyl)methyl]piperidine is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone and 3-bromo-1-phenylpropanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, α-phenyl-4-[(3-ethoxy-2-naphthyl)methyl]-1-piperidinepropanol is obtained.
Reaction SMILES: CC12C(C)(C)C(C([O:13][CH2:14][C@@:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[O:17])=O)(CC1)OC2=O.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].Cl>ClCCl.C(OCC)(=O)C>[CH3:41][S:42]([O:13][CH2:14][C@@:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)=[O:17])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC12CCC(C(=O)OC[C@](C)(O)C(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)(OC1=O)C2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@](O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
439 mg of chiral diol (5C) of Example 22 was dissolved in 20 ml of dichloromethane. The solution was cooled to 0° C. (ice). 170 mg of triethylamine was added. 174 mg of methanesulfonyl chloride was dissolved in 5 ml of dichloromethane and slowly added to the diol solution. After the addition was completed, the mixture was allowed to warm to room temperature. After 25 minutes at room temperature, the reaction mixture was analyzed with HPLC; there was still 27% of diol present. Next 70 mg of methanesulfonyl chloride was added. After 10 minutes at room temperature, the reaction was completed. 60 ml of ethyl acetate and 60 ml of 0.5 N aqueous HCl were added. The organic layer was washed subsequently with 60 ml of water and 60 ml of saturated NaHCO3, dried (Na2SO4), filtrated and evaporated to dryness. Purification of the residue by column chromatography (Merck silica gel 60; eluens: ethyl acetate) afforded the title compound as a green/black oil. Isolated yield: 473 mg. 1H-NMR confirmed the expected structure (2S-enantiomer). HPLC: 94% purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(Cl)Cl.O.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[Cl:18][C:15]1[CH:14]=[C:13]([F:19])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[S:25]([Cl:24])(=[O:27])=[O:26]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2F)c(Cl)c1C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 4-chloro-3-(4-chloro-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 20 mL of chlorosulfonic acid was heated in a 120° C. oil bath for four hours and allowed to cool to room temperature. Methylene chloride was added and the solution added dropwise to a stirring mixture of ice and water (caution, extremely reactive). The layers were separated and the aqueous layer was washed with methylene chloride. The combined organic layers were dried with MgSO4, filtered and concentrated and the resultant solid residue washed with a very small amount of ether and recrystallized from hexanes to afford 1.65 g (63%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenesulfonyl chloride as a white solid; mp 116°-117° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH:15]1([CH2:18][NH:19][C:20](=[O:36])[C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C.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>[Cl:14][C:13]1[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([NH:19][CH2:18][CH:15]3[CH2:17][CH2:16]3)=[O:36])=[CH:22][CH:23]=2)=[CH:3][C:4]([C:5]([NH:7][CH:8]2[CH2:10][CH2:9]2)=[O:6])=[CH:11][CH:12]=1
Reactant: O=C(NC1CC1)c1ccc(Cl)c(Br)c1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1ccc(-c2cc(C(=O)NC3CC3)ccc2Cl)cc1
Temperature: 85 °C

Procedure:
3-Bromo-4-chloro-N-cyclopropylbenzamide (Intermediate 18, 55 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (Intermediate 19, 60 mg), tetrakis(triphenylphosphine)palladium (5 mg) and aqueous sodium carbonate (2N, 0.5 ml) were mixed in DMF (1.2 ml) and heated at 85° C. under nitrogen for 18 hrs. Ethyl acetate was added to the cooled reaction, the reaction filtered and the filtrate reduced to dryness under vacuum. The residue was applied to a SPE cartridge (Si, 5 g) and eluted with an ethyl acetate/cylohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum to give 6-chloro-N3-cyclopropyl-N4′-(cyclopropylmethyl)-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[C:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[N:32]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:24]=[C:25]3[CH2:30][CH2:29][N:28]([C:38]([NH:37][C:33]4[N:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[O:39])[CH2:27][CH2:26]3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(C3CC3)cn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.8 %

Procedure:
To a solution of 5-cyclopropyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (0.972 g, 3.17 mmol) in CH3CN (10 mL) was added phenyl pyridazin-3-ylcarbamate (0.751 g, 3.49 mmol) followed by diisopropylethylamine (2.76 mL, 15.9 mmol). The reaction was stirred at room temperature for 3 d. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-15% EtOH/CH2Cl2) to afford the title compound as a white foam (1.19 g). Recrystallization from hot diisopropyl ether with a few drops of methanol afforded the title compound as an off-white solid (0.857 g, 63% yield). MS (APCI 10V) AP+2 428.09; 1H NMR (400 MHz, CDCl3) δ ppm 0.61-0.67 (m, 2H) 0.93-0.99 (m, 2H) 1.82-1.90 (m, 1H) 2.45 (t, 2H) 2.59 (t, 2H) 3.54 (t, 2H) 3.64 (t, 2H) 6.39 (s, 1H) 6.79-6.82 (m, 1H) 6.92-6.96 (m, 1H) 6.96-7.01 (m, 2H) 7.30-7.35 (m, 2H) 7.38-7.42 (m, 1H) 7.73 (br. s., 1H) 8.01 (d, 1H) 8.29 (d, 1H) 8.82 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:28][O:27][C:22](=[O:26])[CH:23]([O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][C:4]=2[F:16])=[CH:12][CH:11]=1)[CH3:25]
Reactant: COC(=O)C(C)O
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 189.6 %

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)-phenol (2.83 g, 0.01 mol), the methanesulfonate of S methyl lactate (18.2 g, 0.01 mol), and potassium carbonate (1.67 g, 0.012 mol) in DMSO (70 ml) was stirred at room temperature for 40 hours, then poured into water (700 ml). The mixture was extracted with ether (2×200 ml). Pentane (100 ml) was added to the combined ether extracts and the resulting solution washed with water (300 ml). The organic phase was dried (MgSO4) and the solvent evaporated to give a light yellow oil (~7 g). This oil was purified via prep HPLC (8:2 hexane-acetone) with the first peak being collected. Removal of the solvent gave the desired product enriched in the "R" enantiomer; Optical rotation=+20.34° @ 25° C. RI=1.5614 @ 25° C.; NMR (CDCl3) was identical with that obtained in Example 4. No attempt was made to determine the optical purity of this material.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18](=[O:21])[CH2:19]Cl)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[ClH:1].[ClH:1].[N:22]1([CH2:2][C:3]([C:5]2[CH:17]=[CH:16][C:15]3[C:14]4[C:9](=[CH:10][C:11]([C:18](=[O:21])[CH2:19][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:12][CH:13]=4)[CH2:8][C:7]=3[CH:6]=2)=[O:4])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CN3CCCCC3)ccc1-2
Reaction time: 36 h

Procedure:
A mixture of 19.0g (0.06 mole) of 2,7-bis(chloroacetyl)fluorene, 10.2g (0.12 mole) of piperidine and 25.4g (0.24 mole) of sodium carbonate in 300 ml of tetrahydrofuran was gently refluxed with stirring for 36 hours then filtered and concentrated in vacuo. The residue was extracted with ether and this solution was treated with ethereal hydrogen chloride to give the desired product which was recrystallized from methanol-butanone-ether. M.P. 302°-304° C (dec.), λmaxH2O 337, E1cm1% 834.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.CN(C)C=O.[CH2:27]([O:30][CH3:31])[C:28]#[CH:29]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:28][CH2:27][O:30][CH3:31]
Reactant: C#CCOC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (200 mg, the compound of Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) at room temperature was added methyl propargyl ether (0.5 ml), cuprous iodide (15 mg) and bis(triphenylphosphine)palladium(II) chloride (30 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (50 ml) and aqueous citric acid solution (50 ml, 20%). The organic layer was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane to provide the title compound as a pale yellow solid m.p. 210° C. decomp.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Cl[CH2:46][C:47]1[CH:56]=[CH:55][C:50]2[N:51]([CH3:54])[N:52]=[N:53][C:49]=2[CH:48]=1.BrCCCCC>>[CH3:54][N:51]1[C:50]2[CH:55]=[CH:56][C:47]([CH2:46][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:21]5[C:12](=[CH:13][C:14]6[O:19][CH2:18][CH2:17][O:16][C:15]=6[CH:20]=5)[O:11][CH2:10]4)[C:2]3=[O:22])=[CH:48][C:49]=2[N:53]=[N:52]1
Reactant: Cn1nnc2cc(CCl)ccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: Cn1nnc2cc(CN3C(=O)C4(COc5cc6c(cc54)OCCO6)c4ccccc43)ccc21

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 5-(chloromethyl)-1-methyl-1H-benzo[d][1,2,3]triazole to replace 1-bromopentane, 1′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (15%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.6, 1.2 Hz, 1H), 7.20-7.28 (m, 1H), 7.18 (d, J=6.9 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.02 (t, J=7.4 Hz, 1H), 6.54 (s, 1H), 6.08 (s, 1H), 5.10 (ABq, 2H), 4.77 (ABq, 2H), 4.28 (s, 3H), 4.22-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 154.7, 145.2, 144.2, 142.0, 137.8, 132.9, 132.4, 131.7, 128.8, 126.7, 123.7, 123.1, 121.2, 117.6, 111.3, 110.9, 109.5, 98.9, 79.4, 64.2, 63.6, 57.3, 43.1, 34.2; MS (ES+) m/z 440.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:29][S:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:24]=1
Reactant: CSc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: CSc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Yield: 60.5 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (1.37 g, 5.0 mmol) synthesized in Reference example 61 and 4-bromothioanisole (1.52 g, 7.5 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 1.2 g (yield 60%). Melting point was 211 to 213° C. (ethanol).