Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].C(=O)(O)[O-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O.O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of (S)-(+)-2-amino-1-propanol (200 g, 2.66 mol) in purified water (400 mL) was added sodium bicarbonate (246 g, 2.93 mol). To this mixture was added benzyl chloroformate (500 g, 2.93 mol) in tetrahydrofuran (800 mL) at an internal temperature of 20° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated under reduced pressure. The residue was crystallized from petroleum ether to give the target product as a white solid (403 g, yield 72.3%).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>COCCOC>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: OCC1OC2CC(O)CC(C2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.50 g (0.05 mols) of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one of the formula Ia in 90 ml of ethylene glycol dimethyl ether is added dropwise within 15 minutes, while stirring and cooling with ice, to a suspension of 2.0 g (0.05 mols) of lithium aluminium hydride in 60 ml of ethylene glycol dimethyl ether. The reaction mixture is boiled for 15 minutes under reflux, cooled to room temperature and carefully treated with 10 ml of ethyl acetate to destroy excess lithium aluminium hydride. Then, while stirring, 2.0 ml of water, 2.0 ml of 15% sodium hydroxide solution, and finally 6 ml of water, are added to the reaction mixture. The precipitated salts are filtered off, stirred with 100 ml of methylene chloride and filtered again. The combined filtrates are concentrated in a water jet vacuum. The crystalline residue is recrystallised from methylene chloride to give 3-hydroxymethyl-2,4-dioxabicyclo[3,3,1]nonan-7-ol of the formula IIa ##SPC9##
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cccc(F)c4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12h and 4-bromoanisole
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@@H:28]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[C:29]([O:31]C)=[O:30])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@@H:28]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=4)[C:29]([OH:31])=[O:30])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of methyl (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (87 mg, 0.16 mmol) in tetrahydrofuran (2 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 12 hr. The mixture was adjusted to pH 6.5 with 1N hydrochloric acid (4 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to give (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionic acid (61 mg, yield 74%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=O)[NH:10][N:11]=[CH:12][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:2]=3[F:1])=[N:14][C:13]=2[CH:12]=[N:11][N:10]=1
Reactant: O=c1[nH]ncc2nc(Oc3ccc(F)cc3F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Oc2ccc3c(Cl)nncc3n2)c(F)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(2,4-difluorophenoxy)pyrido[3,2-d]pyridazin-5(6H)-one (1.00 g, 3.63 mmol) in POCl3 (8.00 mL, 85.82 mmol) was heated at 95° C. for 4 h. The excess POCl3 was removed under reduced pressure and the crude residue was treated with ice and 1N NaOH. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether to provide 5-chloro-2-(2,4-difluorophenoxy)pyrido[3,2-d]pyridazine as a tan amorphous solid. MS (ESI, pos.ion) m/z: M+1=294.0
Reaction SMILES: OCCC[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:48](=[O:49])[C:47]2C1=CC=C[CH:46]=2)=O.C(=O)(O)[O-].[Na+].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:48]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:35](=[O:36])[C:14]2=[CH:15][N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:26][CH:25]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]2=[N:12]1)(=[O:49])[CH2:47][CH3:46]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CCCO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.5 h

Procedure:
(±)-2-[2-(Hydroxypropyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 657, 81 mg, 0.17 mmol), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 0.11 g, 0.25 mmol, 1.5 equiv), sodium bicarbonate (71 mg, 0.85 mmol, 5 equiv) and water (8.0 μL, 0.44 mmol, 2.6 equiv) were combined in dichloromethane (8 mL) and stirred vigorously for 30 minutes. Additional Dess-Martin periodinane (0.11 g, 0.25 mmol, 1.5 equiv) was added and the mixture was stirred for an additional 45 minutes. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated) and sodium thiosulfate (3 mL, aqueous saturated) and stirred vigorously for 30 minutes. The mixture was poured into sodium bicarbonate (15 mL, aqueous saturated) and extracted with dichloromethane (2×50 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.37 (1H, dd, J=7.2, 2.2 Hz), 7.94-7.91 (2H, m), 7.74-7.72 (3H, m), 7.57-7.43 (5H, m), 7.35 (1H, d, J=7.6 Hz), 7.31 (2H, d, J=8.4 Hz), 6.47 (1H, m), 5.49 (2H, s), 2.73 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.2 Hz) ppm; high resolution mass spectrometry (ES+) m/z 474.1919 [(M+H)+; calculated for C29H24N5O2: 474.1925].
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:4][CH2:3][CH:2]=[CH2:1])[CH2:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCN(CCC=C)Cc1ccccc1
Temperature: 50 °C
Yield: 151.8 %

Procedure:
12 g Benzylamine and 25 g 4-bromo-1-buten were added to a suspension of 46 g potassium carbonate in 150 mL DMF and the mixture was heated at 50° C. for 16 h. The reaction mixture was cooled to RT, diluted with ethyl acetate, washed with water and brine, dried, concentrated, and purified by chromatographie on silica gel (hexane/ethyl acetate 50:1) to yield 18.3 g of the desired product. (M+H)+: 230
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH2:26][C:25]([Cl:29])([Cl:28])[Cl:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 20 h

Procedure:
Synthesis of the peptide segment is started by making the trichloroethanol ester of Boc-Asp(OBzl)-OH (Shioiri et al., 1989). This is achieved by stirring 1 g (3 mmol) of Boc-Asp(OBzl)-OH (Sigma), 0.4 ml of (3 mmol) 2,2,2-trichloroethanol (Aldrich), 100 mg of DMAP (dimethylaminopyridine; Aldrich), and 576 mg (3 mmol) of EDC (Aldrich) in 50 ml of DCM for 3 h at 0° C. and for 20 h at room temperature. The precipitate is filtered out and the filtrate is diluted with 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 10% aqueous citric acid, water, saturated NaHCO3, water and saturated brine. Then, the ethyl acetate layer is dried over anhydrous Na2 SO4, decanted, and concentrated to give an oil. The crude oily product is purified by washing with petroleum ether to give Boc-Asp(OBzl)-OTce (9). 1H-NMR (CDCl3): 1.45 (9H, s), 2.93 and 3.15 (2H, dd, J=17 Hz and 4.5 Hz), 4.67 and 4.75 (2H, dd, J=12.3 Hz), 4.7-4.75 (1H, m), 5.13 (2H, s), 5.56 (1H, d, J=9 Hz), 7.34 -7.38 (5H, m). FABMS: 454 (M+1)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14](O)=[O:15])([CH3:10])([CH3:9])[CH3:8].[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26]>C(N(CC)CC)C>[C:21]([C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])[C:19]=1[OH:20])[CH2:14][O:15][N:27]([CH2:29][CH3:30])[CH2:25][CH3:26])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCN(O)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)OCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 45.2 %

Procedure:
Following the procedure of Example II, the compound is prepared from 3.17 g of oxalyl chloride, 6.25 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 2.53 g of N,N-diethylhydroxylamine, and 2.53 g of triethylamine. The residue is recrystallized from petroleum ether to give 3.47 g of a white solid: mp 129°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([C:18]#[N:19])[CH:5]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]#[N:19])[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-Cyano-4-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester from step 1 (2.5 g, 8.1 mmol) and phenylboronic acid (2 g, 16.2 mmol) were dissolved in DMF (33 ml) and treated with Et3N (3.1 ml, 17.8 mmol). Argon was bubbled into the solution for 20 min. and then a catalytic amount of PdCl2 (PPh3)2 (285 mg, 0.405 mmol) was added. The reaction mixture was warmed to 90° C. and stirred for 3 hours under argon atmosphere. The reaction was quenched with satd. NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](N(OC)C)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].[CH3:30][Mg]Cl.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:25])[CH3:30])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluoro-N-methoxy-N-methylbiphenyl-2-carboxamide (2.7 g, 6.6 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with 3 M of methylmagnesium chloride in tetrahydrofuran (6.6 mL, 20 mmol) dropwise and stirred at 20° C. for 1 hour. The reaction mixture still contained some starting material and was, therefore, cooled to 0° C., treated with additional 3 M of methylmagnesium chloride in tetrahydrofuran (2.2 mL, 6.6 mmol) dropwise, and stirred at 20 ° C. for 2 hours. The reaction mixture was cooled to 0° C., quenched with 1 M hydrogen chloride in water (26 mL, 26 mmol), poured into 0.1 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0%-20%) gave the desired product (2.3 g, 93%). LCMS for C20H20ClFN3O (M+H)+: m/z=372.1; Found: 371.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].CN(C=O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-ethoxy-3-(4-nitrophenyl)acrylate containing 3.6 wt % DMF (26.07 g corrected, 98.3 mmol) was dissolved in IMS (500 ml) and a solution of NaOH (1.44 g, 36.1 mmol) in water (260 ml) was added. The resulting mixture was stirred at ambient temperature for 18 hr then acidified with 1M HCl (120 ml) and the resulting solid collected by filtration, washed with water (2×100 ml) and suction dried on the filter for 30 mins, followed by vacuum oven drying at 18° C. for 18 hr. 2-Ethoxy-3-(4-nitrophenyl)acrylic acid was thus obtained as an orange solid containing water of crystallisation (18.4 g, 79%).
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[CH3:35][S:36]([O-:38])=[O:37].[Na+]>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][S:36]([CH3:35])(=[O:38])=[O:37])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: CS(=O)[O-]
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.11 g) was added to a solution of the product from Example 27 step b) (0.2 g) in DMF (5 ml), and the solution stirred for 10 min. Sodium methanesulfinate (63 mg) was then added and the mixture stirred for a further 3 hours. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (50 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH2:8])=[N:3]1.CC(C)([O-])C.[Na+].[CH3:15][S:16][C:17]1[N:22]=[C:21](SC)[C:20]2=[N:25][CH:26]=[C:27]([C:28]#[N:29])[N:19]2[N:18]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH:8][C:21]2[C:20]3=[N:25][CH:26]=[C:27]([C:28]#[N:29])[N:19]3[N:18]=[C:17]([S:16][CH3:15])[N:22]=2)=[N:3]1
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Reactant: Cc1nc(N)nn1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2nc(C)n(C)n2)c2ncc(C#N)n2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,5-dimethyl-1H-1,2,4-triazol-3-amine (170 mg, 1.517 mmol) was taken up in 6 ml of anhydrous THF and cooled to 0° C. Sodium tert-butoxide (243 mg, 2.53 mmol) was added and the reaction was stirred at 0° C. for 5 min. Next, a solution of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate (300 mg, 1.264 mmol) in 8 ml of THF was added, and the reaction was brought to rt. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was dissolved in EtOAc. The organic layer was washed once with water, and the aqueous layer was reextracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg) as a yellow solid. The crude material was taken onto the next step without further purification.
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)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:28][C:25]4[CH:26]=[N:27][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:23][CH:24]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Product: FC(F)(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 6-(trifluoromethyl)pyridine-3-carbaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[6-(trifluoromethyl)pyridin-3-yl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.Cl.[CH2:19]([O:23][NH2:24])[CH:20]([CH3:22])[CH3:21]>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:24]/[O:23][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CON
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)/C(=N/OCC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 90 mg, 3.26 mmol) was stirred in methanol (7 mL) and warmed in a 70° C. oil bath. O-Isobutylhydroxylamine hydrochloride (511 mg, 4.07 mmol) was added. After 3 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid methyl ester as a white solid (395 mg, 35%): H1-NMR (400 MHz, CDCl3) δ=0.91 (6H, d, J=6.8 Hz), 2.04 (1H, m), 3.30 (3H, s), 3.91 (3H, s), 4.10 (2H, d, J=6.8 Hz), 7.50 (1H, dd, J=8.2 Hz, J=1.6 Hz), 7.61 (1H, d, J=1.6 Hz), 8.18 (1H, d, J=8.2 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH:22][CH3:23])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:27]([N:29](CC)CC)C>C(O)C>[CH3:23][NH:22][C:17]1[N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH:20]=[C:19]([NH:29][CH3:27])[N:18]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NC)n1
Temperature: 140 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
0.47 g (0.0013 mol) of 4-tert-butyl-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.3 g (0.019 mol) of methylamine hydrochloride and 4.7 ml (0.034 mol) of triethylamine and stirred in an autoclave at 140° C. for 18 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and the insoluble constituents were filtered off under suction. The filtered cake was recrystallized in methanol/diethyl ether. There was obtained 0.15 g (33%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-4-tert-butyl-benzenesulfonamide as white crystals; m.p. 316-318° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH3:33][O:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=O)=[CH:37][CH:36]=1>O1CCCC1>[CH3:33][O:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:37][CH:36]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=CCCC(=O)O)c2ccc(OC)cc2)cc1
Yield: 54.9 %

Procedure:
The reaction was performed as in Example 87 using sodium hydride (56% dispersion in oil; 9.5 g) dimethylsulfoxide (100 mL), (3-carboxypropyl)triphenylphosphonium chloride (35 g); 4,4'-dimethoxybenzophenone (26.4 g); and tetrahydrofuran (100 mL). After the usual work up, the crude acid was crystallized from dichloromethane-hexane to give 15.6 g of 5,5-bis(4-methoxyphenyl)-4-pentenoic acid, mp 113°-114° C. Anal. Calculated for C19H20O4 : C, 73.06; H, 6.45. Found: C, 73.00; H, 6.45.