Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([CH2:30][CH2:31][OH:32])([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.Cl>C(Cl)Cl.O>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:32][CH2:31][CH2:30][C:18]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[O:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:17]2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCOS(=O)(=O)c2ccc(Cl)cc2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 47.6 %

Procedure:
To a solution of 2-[4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol obtained in Reference Example 2 (2.0 g, 3.8 mmol) in methylene chloride (20 ml) were added dimethylaminopyridine (0.05 g, 0.38 mmol) and triethylamine (0.8 ml, 5.7 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., and then a solution of 4-chlorobenzenesulfonyl chloride (0.96 g, 4.5 mmol) in methylene chloride (6 ml) was further added dropwise at below 10° C. After stirring at 0-5° C. for 6 hours, water (20 ml) and concentrated hydrochloric acid (0.5 ml) were added to the reaction mixture, and the resulting mixture was partitioned. The separated organic layer was washed with water (20 ml) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column and then crystallized from a mixed solvent of ethyl acetate (2.4 ml) and methylcyclohexane (24 ml) under ice-cooling to afford the title compound [1.3 g, yield: 47.6%] as a colorless crystalline solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C1COCC1.CCCCCC>[CH2:17]([C:12]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:1][CH2:2][CH3:3]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Reactant: CCCCCCCCBr
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of 25.0 g of fluorene in 200 ml of THF at −78° C. was added dropwise 220 ml of 1.6 M butyllithium solution in hexane. The mixture was stirred at this temperature for 1 h and was then allowed to warm to 15° C. The temperature was cooled down to −78° C. again and 77.7 g of n-octyl bromide was added dropwise into the mixture. The solution was allowed to warm to room temperature and was stirred at room temperature for 12 h. The mixture was poured into water and was extracted with ether. The combined extracts were washed with water and brine and were dried over anhydrous magnesium sulphate. The solvent was removed by rotary evaporation. Distillation under reduced pressure gave 50 g of 9,9-dioctylfluorene as a pale yellow oil (212-214° C./2 Toor) (yield 85.2%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](Cl)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])[C:2]#[C:3][CH3:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(OCC)(=O)C.O>CN1CCCC1=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:10]2[C:9]3[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:6](=[O:16])[N:7]([CH3:15])[C:8]=3[CH:13]=[CH:12][N:11]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(=O)n(C)c2ccnc(Cl)c21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(=O)n(C)c2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 180 °C
Yield: 31.6 %

Procedure:
A solution of 3-(2-butynyl)-4-chloro-1-methyl-1,3-dihydroimidazo[4.5-c]pyridin-2-one (compound 82d) (0.865 g) and piperazine-1-carboxylic acid t-butyl ester (4.57 g) in 1-methyl-2-pyrrolidone (2 mL) was heated at 180° C. for two hours under a nitrogen atmosphere. Piperazine-1-carboxylic acid t-butyl ester (5.00 g) was then added again, and this was heated at 180° C. for five hours. Ethyl acetate (400 mL) and water (200 mL) were added, and the organic layer was washed twice with 200 mL of water and then once with 200 mL of saturated aqueous sodium chloride solution, and then was dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography. The ethyl acetate:hexane 3:2 fraction gave the title compound (0.447 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:33].[H-].[Na+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[N:10]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:9]1=[O:33]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (972 mg, 2 mmol) (prepared as described in Example 81) was suspended in 1-methyl-2-pyrrolidinone (15 mL), and sodium hydride (88 mg, 2.2 mmol (60% oil dispersion)) was added. The reaction mixture was stirred at room temperature for 30 minutes, methyl bromoacetate (0.190 mL, 2 mmol) was added. The mixture was stirred for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. :The residue was purified by column chromatography on silica gel using 70:30 hexane/acetone as eluant. The fractions containing the product were combined and evaporated under reduced pressure to give 425 mg of 3-(2-chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexylamino)-1-methoxycarbonylmethyl-3,4-dihydropyrimido-[4,5-d]pyrimidin-2(1H)-one as a white solid ((M+H)+560, m.p.165.7-167.4° C.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1)=[O:2].[CH3:14][Mg]I>C1COCC1>[OH:2][CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1)[CH3:14]
Reactant: O=Cc1cc(-c2ccccn2)no1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2ccccn2)no1
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(5-formyl-isoxazol-3-yl)-pyridine (3 gm) in THF (30 ml) was added methyl magnesium iodide (19 ml, 1.4 M solution in THF) at 0° C. over a period of 15 minutes. The reaction was stirred for 1.5 h and monitored by TLC. The reaction was quenched by addition of aqueous ammonium chloride solution (20 ml) and extracted with ethyl acetate (100 ml×2). Combined organic layers was washed with water and evaporated under vacuum to provide 1.9 gm crude mass, which was purified by using silica gel column chromatography to provide a title compound in 1.0 gm quantity (42%) as a solid.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:35]2)=[CH:30][CH:29]=1
Reactant: NNc1ccc(F)cc1
Reactant: N#CC(C#N)=NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(-c2ccc(F)cc2)c(N)c1N=Nc1ccccc1
Reaction time: 4 h

Procedure:
1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-fluorophenylhydrazine hydrochloride (81 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. After reacting for 4 hrs, very little solid had formed; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was removed by filtration and the solvent was evaporated from the filtrate to yield 29 mg (20%) of the compound as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Reactant: NC(=O)C1CCNCC1
Solvent: Oc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(F)cc23)CC1
Yield: 90.3 %

Procedure:
A mixture of 4.4 g (15 mmol) of 4-chloro-2-(4-chlorophenyl)-6-fluoroquinoline, 3.9 g (30 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 165°-180° for 2 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching. The solid was collected and washed with ether to give 5.2 g of crude product, mp 258°-260° dec. Recrystallization from pyridine/water gave off-white needles, mp 259°-261°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#N.Cl.[OH2:20]>C(OCC)C.CC(O)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[C:13]([C:11]([C:13]2[C:14]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH3:9])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: N#Cc1cccnc1
Reactant: COc1ccccc1Br
Reactant: O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1ccccc1-c1ncccc1C(=O)c1cccnc1-c1ccccc1OC
Reaction time: 0.25 h

Procedure:
A solution of 2-bromoanisole (21 g, 0.11 mol) in diethyl ether (100 mL) was added to magnesium turnings during 45 minutes with heating. After the addition the reflux was continued for 15 min. The Grignard reagent was cooled to 0° C. and a solution of 3-cyanopyridine (10 g, 0.10 mol) in diethyl ether (100 mL) was added dropwise. The mixture was refluxed for a few minutes. Hydrochloric acid (20 mL, 0.24 mol, conc.) and 2-propanol (20 mL) were added and the reflux was continued for 30 min. Water and diethyl ether were added and the phases separated. The water-phase was made alkaline (2M NaOH) and was extracted with diethyl ether. The combined organic phases were dried (MgSO4) and evaporated to yield 17 g. The crude was chromatographed on silica (toluene-ethyl acetate 19:1) to give 3.75 g (19%). 1H NMR (CDCl3-d) δ3.76 (s, 3H), 7.01 (d, 1H), 7.10 (t, 1H), 7.41 (dd, 1H), 7.46 (dd, 1H), 4.53 (m, 1H), 8.12 (d, 1H), 8.75 (s, 1H) and 8.94 (s,
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH2:8]([N:15]1[C:19]2[CH2:20]C[C:22](=[O:23])[C:18]=2[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C.O1CCCC1.O>[CH2:8]([N:15]1[C:19]2[CH2:20][C:7](=[CH:6][OH:5])[C:22](=[O:23])[C:18]=2[CH:17]=[N:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC=O
Reactant: O=C1CCc2c1cnn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(=CO)Cc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.44 grams of a 60% suspension in mineral oil), 1.46 ml of ethyl formate and 3 drops of ethanol were combined in 150 ml of anhydrous tetrahydrofuran and stirred at room temperature for 30 minutes. A solution of 4 grams of 1-benzyl-5,6-dihydro-4(1H)-cyclopentapyrazolone in 50 ml of anhydrous tetrahydrofuran was added dropwise and the reaction mixture was heated at reflux for 16 hours. An additional 1.44 grams of sodium hydride suspension and 1.46 ml of ethyl formate were then added and the reaction mixture was heated at reflux for 2 hours. The mixture was cooled, diluted with 150 ml of water, and washed with ethyl ether. The aqueous layer was acidified with aqueous hydrochloric acid and the solid which formed was collected by filtration to give 1-benzyl-5,6-dihydro-5-hydroxymethylene-4(1H)-cyclopentapyrazolone as a tan solid melting at about 171°-172° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:8][C:7]=2[CH:31]=1)#[N:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (60 mg, 0.144 mmol) in THF (2.1 mL) under nitrogen at −78° C. was added LiHMDS (0.359 ml, 0.359 mmol) in THF. After 10 mins, ethyl chloroformate (0.276 mL, 2.87 mmol) was added and the reaction was warmed to room temperature. After 5 mins the reaction was quenched with sat. aq. NH4Cl, the layers were separated and the aqueous layer extracted with EtOAc. The EtOAc layer was concentrated, purified via FCC with Hep/EtOAc to obtain the title compound. MS (ESI+) m/z 490.0 (M+H).
Reaction SMILES: Cl.NO.[C:4]([C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:21]([N:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:24]2[CH2:29][C@@H:28]([C:30]3[N:31]=NN[N:34]=3)[CH2:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25]2)=[O:22])=[CH:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5].C1C[O:49][CH2:48]C1>CO.C(N(CC)CC)C.O>[C:4]([C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:21]([N:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:24]2[CH2:29][C@@H:28]([C:30]3[N:31]=[CH:48][O:49][N:34]=3)[CH2:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25]2)=[O:22])=[CH:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2nn[nH]n2)CN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2ncon2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (35 mg) was dissolved in THF (3 ml)-methanol (3 ml), triethylamine (0.07 ml) was added, and the mixture was stirred at room temperature for 1 hr. A solution of tert-butyl (3S*,5R*)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(2H-tetrazol-5-yl)piperidine-1-carboxylate (120 mg) in THF (3 ml) was further added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in trimethyl orthoformate (5 ml), 4-methylbenzenesulfonic acid (20 mg) was added and the mixture was stirred at 100° C. for 10 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. The fraction eluted with ethyl acetate-hexane (5:95-50:50) was concentrated under reduced pressure to give the object compound (72.6 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:15][CH3:16])[CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1OCC(=O)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1OCC(O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanone Part B (1.7 g, 5.96 mmol) in THF (12 mL) and MeOH (12 mL) was slowly added sodium borohydride (0.226 g, 5.96 mmol). After stirring at RT for 30 min, the mixture was concentrated, diluted with EtOAc, washed with sat NaHCO3, 1N HCl, brine, dried (Na2SO4) and concentrated. The crude product was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 50:50 gradient) to afford the desired product 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanol 16C (1.53 g, 5.33 mmol, 89% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ 6.97-7.07 (2H, m), 6.81 (1H, d, J=8.53 Hz), 4.14 (1H, dd, J=9.79, 2.76 Hz), 3.90-3.98 (1H, m), 3.85 (3H, s), 3.31 (1H, t, J=2.51 Hz), 2.78 (1H, s), 0.88-1.01 (1H, m), 0.49-0.67 (2H, m), 0.44 (1H, dd, J=9.41, 4.64 Hz), 0.25-0.33 (1H, m).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:24]=1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:24]=1[C:25]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:26]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (19.0 mg, 23.4%). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1H NMR (CDCl3): 7.89-7.79 (m, 2H), 7.74 (s, 1H), 7.55-7.37 (m, 1H), 7.21-7.05 (m, 1H), 5.25-5.09 (m, 1H), 4.25-3.51 (m, 6H), 3.50-2.95 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(N(C)C)=O>[CH2:17]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11]1)[CH3:18]
Reactant: CCOC(=O)CCCBr
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCOc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2
Temperature: 115 °C
Reaction time: 1.5 h

Procedure:
1.0 g (3.3 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethyl-methanesulfonamide (Example 1g) was stirred at 80-90° C. for 30 min with 0.455 g of powdered potassium carbonate in 50 ml of DMA. 0.71 g (0.55 ml, 3.6 mmol) of ethyl 4-bromobutyrate was then added at 60° C. and the mixture was stirred at 115° C. for 90 min. It was then concentrated in vac., the residue was treated with water and aqueous hydrochloric acid, the mixture was taken up in EA, the solution was dried and concentrated, and the residue was chromatographed on silica gel using n-heptane/EA (3:1). Appropriate fractions were crystallized using petroleum ether, 0.74 g, m.p. 40-42° C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[OH-:16].[CH3:17][N+:18]([CH3:21])([CH3:20])[CH3:19]>CO>[CH3:17][N+:18]([CH3:21])([CH3:20])[CH3:19].[F:1][C:2]1[C:7]([S:8]([O-:16])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: [OH-]
Agent: C[N+](C)(C)C
Solvent: CO
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 100 ml of methanol was dissolved 25 g of pentafluorobenzenesulfonyl chloride under ice-cooling and 10 g of an aqueous solution of 25% tetramethylammonium hydroxide was slowly added to the solution. When the mixture was stirred for 3 hours at room temperature, a solution of a pentafluorobenzenesulfonic acid tetramethylammonium salt was obtained. The solution was used for the salt-exchange of a sulfonium salt and an iodonium salt.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]([O:25]CC)=[CH2:24])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:28])[CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH3:29].C([O-])(O)=O.[Na+]>CO>[F:2][C:3]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=[O:25])[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:28])[CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH3:29]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
2 mL of 3N HCl solution was added to a solution of 3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-6-(1-ethoxy-vinyl)-imidazo[1,2-b]pyridazine in 10 mL of MeOH. The reaction solution was stirred at rt for 3 h and then neutralized with saturated NaHCO3 solution. Solvent was evaporated and the residue was purified by chromatography (DCM: MeOH=10:1) to give the title compound as yellow solid (30 mg, 41%). LCMS (method C): [MH]+=355.9, tR=3.75 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4].[OH-].[K+].[C:17](Cl)(Cl)=[O:18]>C1(C)C=CC=CC=1.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:17](=[O:18])[NH:1]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N[C@@H](Cc2ccc([N+](=O)[O-])cc2)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from step (b) (4.9 g) was suspended in toluene, the suspension cooled to 0° C. and a solution of potassium hydroxide (7.0 g) in water (56 ml) added dropwise. A solution of phosgene (62.5 ml of a 12% w/v solution in toluene) was added dropwise to the resulting solution over 30 minutes and stirring continued for 1 hour. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried and evaporated in vacuo to give a yellow oil. Crystallisation from ethyl acetate gave the desired product as pale yellow crystals (2.3 g).