Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH3:27][C:28]1([CH3:40])[O:33][CH2:32][CH:31]([CH2:34]OS(C)(=O)=O)[CH2:30][O:29]1>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:27][C:28]1([CH3:40])[O:33][CH2:32][CH:31]([CH2:34][O:26][C:4]2[C:5]([CH3:25])=[CH:6][C:7]([C:9]3[N:13]=[C:12]([C:14]4[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH:15]=4)[O:11][N:10]=3)=[CH:8][C:3]=2[CH2:1][CH3:2])[CH2:30][O:29]1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1OCC1COC(C)(C)OC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (200 mg, 0.569 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (290 mg, 1.71 mmol) is added. The mixture is stirred at 60° C. for 24 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 4-{3-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-isobutyl-6-methyl-pyridine which is dissolved in THF (5 mL), water (0.5 mL) and TFA (0.25 mL). The solution is stirred at rt for 1 h before the solvent is evaporated. The remaining residue is separated by chromatography on prep. TLC plates with DCM containing 10% of MeOH to give 2-{2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxymethyl}-propane-1,3-diol (20 mg) as a colourless oil; LC-MS: tR=0.86 min, [M+1]+=440.12.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[F-].[K+].[CH3:21][C@@H:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1>CS(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C@@H:22]3[CH3:21])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=[N:5]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Cn2ncc([N+](=O)[O-])c2Cl)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Cn2ncc([N+](=O)[O-])c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Temperature: 100 °C
Yield: 88.1 %

Procedure:
To a solution of 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (268 mg, 1.0 mmol) and potassium fluoride (232 mg, 4.0 mmol) in dry DMSO (20 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (230 mg, 1.15 mmol) and the mixture heated in the microwave at 100° C. for 8 hr. The mixture was partitioned between water (30 mL) and EtOAc (50 mL) and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S)-tert-butyl 4-(1-(4-methoxybenzyl)-4-nitro-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a yellow gum (380 mg). To a solution of this gum (371 mg, 0.86 mmol) in ethanol/water (20 mL/2 mL) was added ammonium chloride (230 mg, 4.3 mmol) and iron powder (192 mg, 3.44 mmol.) and the mixture heated at 80° C. for 1.5 hr. The mixture was cooled, filtered through Celite® and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (40 mL) and the organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave (S)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a red gum (330 mg, 84% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.17-7.11 (m, 3H), 6.82 (d, J=8.6 Hz, 2H), 5.34 (d, J=14.4 Hz, 1H), 5.17 (d, J=14.4 Hz, 1H), 3.98-3.80 (m, 2H), 3.78 (s, 3H), 3.23 (ddd, J=9.9, 6.4, 3.3 Hz, 1H), 3.01 (td, J=11.4, 3.0 Hz, 1H), 2.92-2.83 (m, 1H), 2.66 (s, 1H), 2.57 (s, 1H), 1.47 (s, 9H), 0.81 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(CC3C=CC=CC=3)(=O)=O)[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)Cc1ccccc1
Product: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccccc1

Procedure:
Prepared by the method of example 30, using the product from example 56 part (a) and benzeneacetyl chloride to give the title compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O>CS(C)=O>[O:31]1[C:28]2([CH2:27][CH2:26][N:25]([C:10](=[O:9])[CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[CH2:30][CH2:29]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(=O)CC2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)CO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Trimethylsulfoxonium iodide (2.02 g, 9.20 mmol) was gradually added to a suspension of sodium hydride (385 mg, 9.64 mmol) in dimethylsulfoxide (50 ml), and the resultant mixture was stirred at room temperature for 1 hour. To which tert-butyl 4-[2-oxo-2-(4-oxopiperidin-1-yl)ethyl]piperazine-1-carboxylate (2.85 g, 8.76 mmol) in DMSO (10 ml) was added, and the mixture was stirred at room temperature for 2 hours, and stirred at 55° C. for 1 hour. The reaction mixture was poured into iced water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The resultant filtrate was concentrated under a reduced pressure to afford tert-butyl 4-[2-(1-oxa-6-azaspiro[2,5]octan-6-yl)-2-oxoethyl]piperazine-1-carboxylate (2.97 g, yield 99%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:25]1([CH2:24][NH:31][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[CH2:10][C:3]=23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(CNc2ccnc3c2CC2(CN4CCC2CC4)O3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A solution of 97 mg (0.387 mmol) of 4'-chlorospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] in 5 mL of benzylamine was heated to reflux under a nitrogen atmosphere and stirred for 18 hours. Upon cooling to ambient temperature, the diluted with 40 mL of water, basicified with 2 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel using a 9:1 mixture of ammoniated chloroform/methanol to provide 42 mg (34%) of the title compound as a white solid: electrospray MS (m/z, relative intensity) 322 ([MH]+).
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][O:6][C:5]([CH:8]([CH3:10])[CH3:9])=[N:4]1.O=S(Cl)Cl>ClCCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1
Reactant: CC(C)C1=NC(O)(CCl)CO1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)c1nc(CCl)co1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
A solution of 4-chloromethyl-4-hydorxy-2-isopropyloxazoline (4.88 g, 0.0275 mol) in 1,2-dichloroethane (20 mL) was added to a solution of SOCl2 (2.40 mL, 0.0329 mol) in 1,2-dichloroethane (80 mL) at 0° C. under argon, and the solution was heated to 70° C. After 15 min at 70° C., the reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. Drying the residue on high vacuum gave the desired compound as a brown semi-solid (4.20 g, 0.0263 mol, 96%): 1H NMR (CDCl3) δ 1.36 (d, J=7.5 Hz, 6H), 3.03-3.18 (m, 1H), 4.50 (s, 2H), 7.56 (s, 1H). Mass spectrum: (M+H)+ =160, 162.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[H][H]>[Pd].CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(C(CCCCBr)c2ccc(F)cc2)cc1

Procedure:
A mixture of 92 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene] and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 84 parts of 1,1'-(5-bromo-1-pentylidene)bis[4-fluorobenzene] as a residue (int. 51).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:29])=[O:13]>CO.C1COCC1.[Pd]>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:29])=[O:13]
Reactant: CC1c2nnn(-c3cnccn3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1c2nnn(-c3cnccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 8 h

Procedure:
A suspension of the 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-methyl-1-pyrazin-2-yl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine (150 mg, 0.36 mmol) in MeOH (3.0 mL) and THF (1.0 mL) was treated with 10% Pd/C (30 mg), put under an atmosphere of H2 and stirred overnight. The reaction was filtered through Celite© and purified on 12 g SiO2 with 0-70% EA/DCM. MS (ESI): mass calcd. for C18H14ClF3N6O, 422.1. m/z found, 423.1 [M+H]+.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[CH2:5][CH2:4]1)=O.[OH-].[Na+]>Cl.CO>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([CH:6]2[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)[CH:14]=1
Reactant: COc1ccc(F)cc1C1CCN(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1C1CCNCC1
Temperature: 25 °C

Procedure:
The crude product of 1-formyl-4-(5-fluoro-2-methoxy-phenyl)-piperidine (0.80 g, 3.4 mmole) was dissolved in HCl (16 mL, 0.5 N) and MeOH (5 mL), and the mixture was brought to reflux for 16 hours. The mixture was cooled to room temperature and basified with NaOH (2.5 N), and extracted with EtOAc (3×25 mL) to give 4-(5-fluoro-2-methoxy-phenyl)-piperidine which was used directly without further purification.
Reaction SMILES: C([Mg]Br)C.C(NC(C)C)(C)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[CH2:20]([O:27][C:28]1[CH:35]=[C:34]2[C:31]([CH2:32][C:33]2([S:38][C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29]=1[O:46][CH3:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.O1CCCC1>[C:16]([O:15][C:12](=[O:14])[CH:13]=[C:36]([NH2:37])[C:33]1([S:38][C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH2:32][C:31]2[C:34]1=[CH:35][C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[C:29]([O:46][CH3:47])[CH:30]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C#N)(Sc1ccc(Cl)cc1)C2
Reactant: CC(=O)OC(C)(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCc1ccccc1)C(Sc1ccc(Cl)cc1)(C(N)=CC(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethylmagnesium bromide (3.26 mL of a 3M solution in diethyl ether, 9.8 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. under nitrogen is added diisopropylamine (2.75 mL, 19.6 mmol). The mixture is stirred at 0° C. for 1 hour. t-Butyl acetate (0.5 mL, 3.6 mmol) and a solution of 1.0 g (2.45 mmol) of 4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile in anhydrous tetrahydrofuran (10 mL) are added successively, and the resulting mixture is stirred for an additional hour. The reaction is quenched with aqueous ammonium chloride and the product mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried over anhydrous sodium sulfate and passed through a plug of silica to give 3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-acrylic acid tert-butyl ester as a clear oil, that solidified upon standing, mp 112-115° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]([CH2:19][CH:20]([OH:23])[CH2:21][F:22])[CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:22][CH2:21][CH:20]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:19][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][CH2:17][O:18][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN(Cc1ccccc1)CC(O)CF
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCN(Cc1ccccc1)CC(CF)OS(C)(=O)=O
Yield: 108.6 %

Procedure:
7.27 g (0.072 mole) of triethylamine were added to a solution of 6.75 g (0.03 mole) of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine [prepared as described in step (a) above] in 200 ml of ethyl acetate. Whilst stirring and ice-cooling the mixture, 8.24 g (0.072 mole) of methanesulfonyl chloride were added to it. After the resulting mixture had been stirred for 3 hours at the same temperature, an aqueous solution of sodium bicarbonate was added to it. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 12.49 g of N-(3-fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([O-:18])(=O)=[O:16])[CH:7]=[CH:6]2.[Na+].S(Cl)([Cl:22])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([Cl:22])(=[O:18])=[O:16])[CH:7]=[CH:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 minutes, the reaction mixture was poured into 1 l of ice water, and the precipitate filtered and then dissolved into 250 ml of benzene. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo, and the residue was recrystallized from benzene-n-hexane (1:1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P. 127.5°-129.5° C
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:9][CH:8]=1.[CH3:30][NH:31][CH3:32].CCOCC>CO>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:9][CH:8]=1
Reactant: CC/C(=C(\c1ccc(I)cc1)c1ccc(OCCCCCl)cc1)c1ccccc1
Reactant: CNC
Solvent: CCOCC
Solvent: CO
Product: CC/C(=C(\c1ccc(I)cc1)c1ccc(OCCCCN(C)C)cc1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of E-1-(4-(4-chlorobutoxy)phenyl)-1-(4-iodophenyl)-2-phenyl-1-butene (0.429 g, 0.83 mmol) and dimethylamine in methanol solution (30 ml, 30%) was heated In a sealed bomb at 100° C. for 2 h, then poured into ether (75 ml), and washed with brine (100 ml) and water (2×100 ml). The organic layer was dried (Na2SO4), and concentrated in vacuo. The residues were purified by flash chromatography (silica; eluant:0-10% methanol in ether) to give the title compound as an off white solid (0.391 g, 89%) mp 74°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:22].CS([C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1)=O.C(N(CC)C(C)C)(C)C>COCCO.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:22][C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(N2CCN(C3CCN(C)CC3)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: CO
Product: COc1cc(N2CCN(C3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 180 °C
Yield: 53.6 %

Procedure:
A solution of 2-methoxy-4-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-phenylamine (140 mg, 0.45 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (65 mg, 0.23 mmol) in 2-methoxyethanol (0.50 mL) was treated with N,N-diisopropylethylamine (59 uL, 0.34 mmol). The reaction was heated under microwave conditions at 300 watts at 180° C. for 90 minutes. The mixture was diluted with methanol (10 mL), filtered and concentrated. The residue was purified by preparative RP-HPLC to give 65 mg of an amber amorphous powder. MS=528 (M-TFA+H); NMR (DMSO-d6, ppm): 10.15 (s, 1H), 9.83 (s, 1H), 8.92 (s, 1H), 7.92 (d, J=9 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.43 (t, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 6.95 (q, J=5 Hz, 14 Hz, 1H), 6.73 (s, 1H), 6.45 (d, J=9 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.61 (m, 4H), 3.48 (m, 2H), 3.22 (m, 2H), 3.00 (m, 4H), 2.80 (s, 3H), 2.67 (m, 1H), 2.37 (m, 2H), 1.88 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCCCCCC>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: CCCCCCC
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 142 °C
Reaction time: 0.03 h

Procedure:
To a 22-L reactor was charged compound 7 (650 g, 1.82 mol), anisole (3.25 L, 5 vol, anhydrous) and benzylamine (600 mL, 0.92 vol, 3 equiv). The batch (approximately 18° C.) was heated to 142±5° C. over 1 hour 44 minutes, with dissolution occurring at 30° C. The batch was maintained at 142±5° C. for 69 hours 30 minutes at which point HPLC analysis indicated that compound 7 was 0.9% by conversion (specification ≦1.7% by conversion). The batch was cooled to 45-50° C. over 5 hours 12 minutes (to aid cooling the nitrogen flow was increased once the batch was approximately 72° C.). At that temperature range, the batch was poorly stirring and on mixing, the batch temperature increased to 52° C. It was >50° C. for <15 minutes. The batch was aged for 2 hours 2 minutes once initially <50° C., then n-heptane (9.75 L, 15 vol, 99%) was added to the batch over 1 hour 56 minutes, maintaining the batch temperature at 45-50° C. The heating was then discontinued and the batch cooled to 25° C. over 10 hours 32 minutes and then to approximately 20° C. over 20 minutes. The total time the batch was maintained ≦25° C. was 4 hours 50 minutes (2 hours 47 minutes at approximately 20° C.). The batch was filtered under suction via a 24-inch polypropylene filter funnel (fitted with a PTFE cloth) and the reactor rinsed with anisole/n-heptane (1.3 L, 4:1) and the rinse transferred to the cake. The cake was then washed successively with two portions of n-heptane (1.3 L, 0.65 L). The total filtration time was 39 minutes. The batch (net wet weight 1004 g of KX2391) was transferred to three glass trays and placed into a vacuum oven set at 50° C. and dried to constant weight over 96 hours 26 minutes.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH:24]=1>>[CH3:22][N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[CH:34][CH:33]=3)=[N:3]2)=[CH:8][CH:9]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(-c4cccnc4)cc3)nn12)S(C)(=O)=O

Procedure:
N-Methyl-N-{2-[2-(4-pyridin-3-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide was prepared from N-[2-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (71 mg, 50%). LCMS (m/e) 471 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.82 (s, 1H), 8.75 (s, 1H), 8.55 (d, 1H, J=4.6 Hz), 8.00-7.91 (m, 1H), 7.83 (d, 1H, J=8.1 Hz), 7.60 (d, 2H, J=7.9 Hz), 7.59-7.49 (m, 3H), 7.45 (d, 2H, J=7.7 Hz), 7.39-7.30 (m, 1H), 7.07 (d, 1H, J=4.0 Hz), 6.95-6.85 (m, 2H), 3.15 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[CH:4]1[O:6][CH2:5]1.[CH3:15][Al](C)C.Cl>ClCCl.CCCCCC>[F:1][C:2]1[C:3]([CH:4]([CH3:15])[CH2:5][OH:6])=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: C[Al](C)C
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F

Procedure:
A solution of 10.5 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 50 ml of dichloromethane was added dropwise to 100 ml of a 1.0M solution of trimethylaluminum in hexane, and was reacted for 40 hours at room temperature. This reaction mixture was poured into 100 ml of 1N hydrochloric acid. After the aqueous layer was extracted with ether, the total organic solution was dried over magnesium sulfate. The solvent was distilled out under reduced pressure, and the subsequent distillation under reduced pressure gave 10.6 g of (+)-2-(pentafluorophenyl)-1-propanol having the aforementioned physical properties.