Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: Clc1ccc2cc[nH]c2c1
Product: FC(F)(F)c1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-3-(trifluoromethyl)benzene: ESMS m/e: 295.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35](N)=[O:36])[CH:30]=2)[N:4]=1.Cl.C1C[O:42]CC1>C1COCC1.O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:42])=[O:36])[CH:30]=2)[N:4]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(N)=O)c2)nc1OC
Reactant: C1CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC

Procedure:
1 g of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid amide, product of example 20, dissolved in a mixture of THF/dioxane (40 ml/30 ml) were treated at RT with 3N HCl (40 ml) and the solution was refluxed for 24 h, further THF (12 ml) and 3M HCl (12 ml) was then added and the solution was heated to reflux for further 24 h until the transformation was complete according to TLC analysis. The reaction mixture was concentrated in vacuo and the product was extracted into CH2Cl2. The organic layer was dried over Na2SO4, the solvent removed in vacuo. The remaining crystalline solid was washed with ether and dried in a vacuum to give 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid as an off-white solid. ISN mass spectrum, m/e 522 (M−1 calculated for C24H21N5O7S: 522).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH:21]=[O:22])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:43])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH:21]=[O:22])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:34])([F:33])[C:26]([F:31])([F:32])[C:27]([F:30])([F:29])[F:28])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)C(F)(F)F)cc2NC=O)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)C(F)(F)F)cc2NC=O)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
0.7 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-formylamino-3-(2,2,3,3,4,4,4-heptafluorobutoxy)pyrazole was dissolved in 20 mL of chloroform, and 360 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.72 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-formylamino-3-(2,2,3,3,4,4,4-heptafluorobutoxy)pyrazole.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[S:10][C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][N:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C(Cl)Cl>[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@@H:8]([C:9]1[S:10][C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][N:13]=1)[CH3:21])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cnc(/C=N/[S@@](=O)C(C)(C)C)s1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1ncc(C(=O)OC(C)(C)C)s1
Temperature: -70 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of (S,E)-tert-butyl 2-((tert-butylsulfinylimino)methyl)thiazole-5-carboxylate (15 g, 47 mmol) in DCM (500 mL) at −70° C. was slowly added methylmagnesium bromide (63 mL, 3 M in ether). The mixture was stirred at −70° C. for 3 h then quenched with sat. NH4Cl solution. The solution was then warmed to rt. After separation, the aqueous phase was extracted with DCM (3×200 mL). Combined organic phases were dried (Na2SO4), and concentrated. Flash column chromatography (DCM:MeOH, 100:0 to 100:1) afforded tert-butyl 2-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)thiazole-5-carboxylate (10 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 4.76 (m, 1H), 4.15 (m, 1H), 1.60 (d, J=6.8 Hz, 3H), 1.50 (s, 9H), 1.20 (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1ccc(O)c(C(=O)O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOc1ccc(OC(C)=O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.069 mL) was added to a solution mixture of the obtained 2-hydroxy-5-propoxybenzoic acid (0.12 g) in methylene chloride (3.0 mL) and pyridine (0.12 mL) under ice-cooling, followed by stirring at room temperature for 2 hours and 30 minutes. Pyridine (0.050 mL) and acetic anhydride (0.058 mL) were added to the reaction mixture, followed by stirring at room temperature for 50 minutes. The solvent was evaporated under reduced pressure, and 1 mol/L hydrochloric acid and ethyl acetate were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 65-55% hexane/ethyl acetate] to obtain 0.091 g of 2-acetoxy-5-propoxybenzoic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1[C:14]([CH3:18])([CH3:17])[C:15]#[N:16].[C-:19]#[N:20].[K+]>CN(C)C=O>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1[C:14]([CH3:18])([CH3:17])[C:15]#[N:16])#[N:20]
Reactant: [C-]#N
Reactant: CC(C)(C#N)c1cc(Cn2cncn2)ccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cc(Cn2cncn2)ccc1C#N

Procedure:
A mixture of 2-[2-bromo-5-(1H-1,2,4-triazol-1-ylmethyl)-phenyl]-2-methylpropiononitrile (0.15 g), dimethylformamide (2 ml) and cuprous cyanide (0.09 g) was stirred and heated under reflux for 8 h. The cooled mixture was treated with aqueous potassium cyanide solution (10 ml) and the mixture was stirred for 10 minutes, then extracted three times with dichloromethane. The combined extracts were dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography, using methanol (2% by volume) in chloroform as eluant, to give 2-[2-cyano-5-(1H-1,2,4-triazol-yl methyl)phenyl]-2-methylpropiononitrile, characterised as the hydrochloride salt mp 159°-166°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([CH:13]1[CH2:18][CH2:17][N:16](CCC2C=CC(F)=CC=2)[CH2:15][CH2:14]1)[OH:12].C1(OC)C(=CC=CC=1)OC.N1C=CC(C=O)=CC=1>>[OH:12][CH:11]([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc([C@H](O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Agent: O=Cc1ccncc1
Solvent: COc1ccccc1OC
Product: COc1cccc(C(O)c2ccncc2)c1OC

Procedure:
In yet another embodiment, there is provided a process for preparing (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) comprising the steps of: a) reacting lithiated veratrole with 4-pyridinecarboxaldehyde (9) in the presence of a suitable aprotic solvent to provide 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10); b) subjecting 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) to catalytic hydrogenation to provide 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11); c) reacting 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) with a suitable 4-fluorophenylacetylating reagent, in the presence of a suitable base and a suitable solvent to provide 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20); d) reacting 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20) with a suitable reducing agent in the presence of a suitable solvent to provide α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5); e) reacting α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (5) with (2S,3S)-(+)-di-(p-anisoyl)tartaric acid to give a racemic mixture of (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (2S,3S)-(+) -di-(p-anisoyl)tartaric acid salt (3a) and (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (2S,3S)-(+)-di-(p-anisoyl)tartaric acid salt (3b); f) separating the (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (2S,3S)-(+)-di-(p-anisoyl)tartaric acid salt (3b) from the (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (2S,3S)-(+)-di-(p -anisoyl)tartaric acid salt (3a) by selective crystallization; and g) reacting the (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, (2S,3S)-(+)-di-(p -anisoyl)tartaric acid salt (3a) with a suitable base to give (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13](=O)[O:14]C(C)(C)C)([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.CCCCCC>O1CCCC1>[C:8]([O:12][C:13]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCNCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Reaction time: 3 h

Procedure:
A solution of 4-hydroxypiperidine (5.05 g; 0.05 mole) in 100 ml of tetrahydrofuran was stirred and cooled in an ice-water bath. Di-tert.butylcarbonate (10.9 g; 0.05 mole) was added and stirring was continued at room temperature for 3 hrs. The solvent was removed under reduced pressure. An oily residue was triturated with petroleum ether. Recrystallization from petroleum ether yielded 9.21 g (92%). Rf (silica gel)=0.42 (ethyl acetate/n-hexane 1:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]([OH:14])=O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:12](=[O:14])[CH2:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(O)c2[nH]ncc12
Reactant: NCc1ccccc1
Product: O=C(Cc1ccc(O)c2[nH]ncc12)NCc1ccccc1

Procedure:
2.3 g of 2-(7-hydroxy-1H-indazol-4-yl)acetic acid is reacted analogously to Example 19(c) with benzylamine in place of dipropylamine. The product is recrystallized from methanol/diisopropyl ether, thus obtaining 2.6 g of 2-(7-hydroxy-1H-indazol-4-yl)acetic acid benzylamide, mp 188°-190° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:19]2[CH:18]=[CH:17][C:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
To a solution of 6.60 g (0.0330 mole) of N,N-dimethyl-4-hydroxybenzenesulfonamide dissolved in 150 ml of DMSO was added 1.32 g (0.0330 mole) of NaOH. The mixture was heated at 60° C. for 10 minutes and 7.1 g (0.030 mole) of 4-fluorophenyl phenyl sulfone was added. The reaction mixture was heated at 100° C. for 3 hrs and at 125° C. for 3 hrs and cooled. The mixture was poured into a solution of 200 ml of 20% aqueous NaOH and 500 ml of water. The crystalline product was collected, washed well with water and dried, which gave 11.5 g (92% yield) of product. Recrystallization from aqueous DMSO followed by recrystallization from ethanol afforded purified N,N-dimethyl-4-(4-(phenylsulfonyl)phenoxy)benzenesulfonamide, mp 99°-100° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:28](Cl)=[O:29]>CCOCC>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1F
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 3-fluoro-4-hexadecylaminobenzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from diethyl ether to yield 3-fluoro-4-(hexadecylamino)benzoylpiperidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:6]([C@@H:8]([C:12]2[O:13][C:14]3[C:19]([C:20](=[O:29])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=[C:16]([Cl:30])[CH:15]=3)[CH:9]([CH3:11])[CH3:10])[CH:7]=1.N1C=CC=CC=1.[CH3:44][C:45](OC(C)=O)=[O:46]>C(Cl)Cl>[CH2:22]([CH:21]1[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[O:13][CH:12]1[C@H:8]([N:6]1[CH:7]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[CH3:44])[N:4]=[C:5]1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[CH:9]([CH3:11])[CH3:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cn([C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)c(-c2ccc(C)cc2)n1
Yield: 88.8 %

Procedure:
To 2-[(R)-1-(4-aminomethyl-2-p-tolyl-imidazol-1-yl)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.17 g, 0.33 mMol) in CH2Cl2 (5 mL) was added with stirring, pyridine (27 uL, 0.33 mMol) and Ac2O (63 uL, 0.67 mMol). After stirring at RT for 4 h the reaction was concentrated under vacuum. The remaining residue was triturated with (1:1) Et2O/pet. ether, filtered and dried under vacuum to give the title compound (163 mg, 89%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.43 (m, 6H), 7.17 (m, 3H), 6.84 (br s, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.69 (s, 1H), 5.07 (d, J=10.9 Hz, 1H), 4.50 (2d, 1H), 4.43 (2d, 1H), 4.07 (d, J=15.5 Hz, 1H), 2.66 (m, 1H), 2.51 (s, 3H), 2.48 (d, J=15.5 Hz, 1H), 2.00 (s, 3H), 0.95 (d, J=6.6 Hz, 3 H), 0.34 (d, J=6.7 Hz, 3H); MS (ES) m/e 554.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9][CH2:8]1.C(=O)([O-])O.[Na+].FC(F)(F)S(O[CH2:36][CH:37]([F:39])[F:38])(=O)=O>C(O)C.C(Cl)Cl>[F:38][CH:37]([F:39])[CH2:36][N:9]1[CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccn1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(c1ccccn1)O2
Temperature: 80 °C

Procedure:
To tert-butyl 10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (63 mg, 0.19 mmol) in ethanol was added sodium hydrogen carbonate (64 mg, 0.76 mmol) followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (49 mg, 0.23 mmol) and reaction mixture was heated at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature and diluted with DCM and the organic layer was washed with 1:1 NaOH:NaHCO3 solution. The organics were separated, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate as an oil. To the oil was added HCl (237.5 μL of 4 M in dioxane, 0.95 mmol) at room temperature under an atmosphere of nitrogen and the reaction mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue was triturated with ether to give 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane (45 mg, 79%). ESI-MS m/z calc. 297.3. found 298.4 (M+1)+; Retention time: 0.35 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(O)(=O)C.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
4-Fluoro-3-nitro-benzaldehyde (3.39 g, 0.0200 mol) was dissolved in methylene chloride (100 mL) and acetic acid (3.50 mL, 0.0616 mol) and the mixture was cooled to −10° C. Piperidine (2.4 mL, 0.024 mol) was then added to the cooled mixture over 10 minutes. Sodium triacetoxyborohydride (17.0 g, 0.0802 mol) was added in one portion. After stirring at 0° C. for 18 hours, the reaction was poured into a mixture of 1N aqueous HCl and ice. The organic phase was removed, and the aqueous layer was made basic by the addition of NaOH pellets. The aqueous layer was extracted twice with methylene chloride, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in methylene chloride and purified by silica gel chromatography (ethyl acetate/hexanes as eluent) followed by further purification by preparative HPLC to yield 2.69 g of 1-(4-fluoro-3-nitro-benzyl)-piperidine as a TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:27]([NH2:26])=[O:28])[CH2:21][CH2:22]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Yield: 47.2 %

Procedure:
A mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 5.1 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized from ethyl acetate (2×) to yield 2.7 g (47%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 148°-150°.
Reaction SMILES: I[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH2:16]([OH:19])[CH:17]=[CH2:18].C([O-])(O)=O.[Na+].[BH4-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.CO.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)=O>[O-:15][N+:4]1[C:5]2[CH:14]=[C:13]3[C:9](=[CH:8][C:6]=2[N:7]=[C:2]([CH2:18][CH2:17][CH2:16][OH:19])[N:3]=1)[CH2:10][CH2:11][CH2:12]3
Reactant: [O-][n+]1nc(I)nc2cc3c(cc21)CCC3
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Temperature: -40 °C
Yield: 45.4 %

Procedure:
Pd(OAc)2 (18 mg, 0.08 mmol) was added to a degassed solution of iodide 66 (250 mg, 0.80 mmol), allyl alcohol (0.27 mL, 3.40 mmol), tetrabutylammonium chloride (182 mg, 0.80 mmol) and NaHCO3 (147 mg, 1.76 mmol) in acetonitrile (12.5 mL) and the solution irradiated in a Milestone MicroSYNTH reactor for 15 min at 150° C. (max. 400 watt). After cooling, the mixture was quenched with saturated aqueous NH4Cl solution (10 ml) and filtered. The filtrate was extracted with EtOAc (3×20 ml), dried and the solvent evaporated. The crude residue was dissolved in MeOH (20 mL), cooled to −40° C. and NaBH4 (2×40 mg, 2.12 mmol) in MeOH (20 mL) added to it. The solution was stirred at −40° C. for 1, then HOAc (0.1 mL) added, warmed to 20° C. and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (80-100%) EtOAc/pet. ether, to give alcohol 70 (89 mg, 45%) as an off-white solid; spectroscopically identical to the sample prepared above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.O.[NH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][N:13]=[C:8]2[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: NN
Solvent: O
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 130 °C
Yield: 73 %

Procedure:
A solution of 1-(5-bromo-2-fluoro-phenyl)-ethanone (10 g, 46 mmol) in hydrazine hydrate (80 mL) was heated at reflux (130° C.) for 20 hours. The reaction mixture was cooled to room temperature, excess hydrazine hydrate was removed and the crude residue was purified by column chromatography (60-120 mesh silica gel) using 10% ethyl acetate in pet-ether as eluents to obtain 5-bromo-3-methyl-1H-indazole (7.09 g, 73%) as a solid. 1H NMR (CDCl3): δ 10.2-10.6 (br, 1H), 7.8-7.9 (s, 1H), 7.4-7.5 (d, 1H), 7.2-7.4 (d, 1H), 2.5-2.7 (s, 3H).