Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6](O)=[O:7])[CH3:2].B>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:9]=[C:10]([CH3:12])[N:11]=1)[CH3:2]
Reactant: CCc1cc(C(=O)O)cc(C)n1
Agent: B
Solvent: C1CCOC1
Product: CCc1cc(CO)cc(C)n1
Yield: 87.4 %

Procedure:
A suspension of 2-ethyl-6-methyl-isonicotinic acid (2.73 g, 16.5 mmol) in THF (30 mL) is treated with borane in THF (1M, 33.1 mL) at rt for 15 h. The mixture is quenched with sat. aq. Na2CO3 (100 mL) and extracted with CHCl3 (5×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated (50 mbar, 45° C.) to give crude (2-ethyl-6-methyl-pyridin-4-yl)-methanol (2.18 g); LC-MS: tR=0.80 min, [M+1]+=205.32.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][O:28][C:29](ON=C(C2C=CC=CC=2)C#N)=[O:30])=[CH:25][CH:24]=1.O1CCOCC1>O>[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][O:28][C:29]([NH:11][CH2:10][CH2:9][C:8]2[C:12]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=3)[NH:6][CH:7]=2)=[O:30])=[CH:25][CH:24]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc(COC(=O)ON=C(C#N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(COC(=O)NCCc2c[nH]c3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a strirred suspension 1.4 g (7.8 mmol) of 5-fluorotryptamine in 5 mL of water and 1.1 mL (7.8 mmol) of triethylamine was added 2.5 g (7.8 mmol) of 2-(4-methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile (MOZ-ON) and 10 mL of dioxane. The reaction mixture was stirred at room temperature for 1 hour under argon, diluted with water, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography, over silica gel, using hexane:ethyl acetate (2:1 and later 1:1) as eluents to provide 1.7 g (63%) of N-(p-methoxybenzyloxycarbonyl)-5-fluorotryptamine as an off-white solid. mp 118°-119° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(C)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(C)cccc1C
Temperature: 60 °C
Reaction time: 10 h
Yield: 55.2 %

Procedure:
A suspension of 2,6-dimethylphenol (19.5 g), iodomethane (31 ml) and potassium carbonate (33.2 g) in dimethylformamide (200 ml) was stirred at 60° C. for 10 hours. The reaction mixture was poured into water (300 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-methoxy-m-xylene (12 g) as a colorless oil. A suspension of 2-methoxy-m-xylene (5.1 g), N-bromosuccinimide (4.2 g) and bezoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g). The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid-water (1:1, 16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-methoxy-3-methylbenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-methoxy-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:13]=[CH:12]2.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-n2ccc3cc(OCCCCCCBr)ccc32)cc1
Reactant: C1CCNCC1
Product: Fc1ccc(-n2ccc3cc(OCCCCCCN4CCCCC4)ccc32)cc1

Procedure:
In analogy to example 1.4, 5-(6-Bromo-hexyloxy)-1-(4-fluoro-phenyl)-1H-indole and piperidine were converted to yield 1-(4-Fluoro-phenyl)-5-(6-piperidin-1-yl-hexyloxy) -1H-indole as light brown amorphous, MS: 395 (MH+).
Reaction SMILES: COC([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([O:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:11])=[CH:8][CH:7]=1)=O>C(O)C.N>[OH:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([O:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:11])=[CH:8][CH:7]=1
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(OC(=O)OC)cc1
Agent: N
Solvent: CCO
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(O)cc1

Procedure:
Compound 3 (11.6 g, 38 mmol) in ethanol (200 ml) and aqueous ammonia (50 ml) was stirred overnight. The solvents were removed in vacuo and the resulting colourless oil was purified by column chromatography (ethyl acetate) on silica.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:24][CH2:23]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCN(C2CCOCC2)CC1
Yield: 64.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (0.4 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.6 g), the title compound (0.6 g) was obtained. melting point: >285° C.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.ClCCl>[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: N[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 135 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of tert-butyl 4-fluorobenzoate (1, 1.00 g, 5.1 mmol), (S)-3-aminopyrrolidine (1.5 eq) and K2CO3 (0.84 g, 6.1 mmol, 1.2 eq.) is suspended in 4 mL of anhydrous DMSO. The suspension is stirred at 135° C. under N2 for 16 h in a sealed flask, cooled to room temperature, diluted with dichloromethane (300 mL) and successively washed with saturated aqueous NaHCO3 and water, dried over MgSO4, filtered and concentrated in vacuo to afford title compound 17 (1.22 g, 91% yield). 1H NMR: (DMSO-d6) δ(ppm): 7.65 (d, J=8.8 Hz, 2H), 6.47 (d, J=9.0 Hz, 2H), 3.65 (quint, J=5.3 Hz, 1H), 3.40 (t, J=9.8 Hz, 1H), 3.38 (t, J=9.8 Hz, 1H), 3.29-3.23 (m, 1H), 2.91 (dd, J=9.8, 4.7 Hz, 1H), 2.03 (sext, J=5.9 Hz, 1H), 1.74-1.63 (m, 3H), 1.48 (s, 9H). m/z: 263.1 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A 5 mL pear-shaped flask was charged with N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (134 mg, 0.30 mmol), phenol (85 mg, 0.90 mmol), potassium carbonate (250 mg, 18.0 mmol), and DMA (0.9 mL). The heterogeneous solution was heated to 150° C. and stirred overnight. The crude reaction mixture was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.75 (d, 1H), 7.72 (d, 2H), 7.48 (d, 2H), 7.28-7.34 (m, 2H), 7.17-7.21 (m, 1H), 7.05 (bs, 1H), 6.71-6.76 (m, 2H), 1.34 (s, 9H); MS (ES) M+H expect 417.1. found 417.4.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:4][S:5]([CH3:8])(=[O:7])=[O:6].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]([OH:40])[CH:25]([NH:28][C:29](=[O:39])[CH:30]([NH2:38])[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]([OH:40])[CH:25]([NH:28][C:29](=[O:39])[CH:30]([NH:38][C:3](=[N:4][S:5]([CH3:8])(=[O:6])=[O:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:26][CH3:27]
Reactant: CCC(NC(=O)C(N)CC1CCCCC1)C(O)c1nc2ccccc2o1
Reactant: COC(=NS(C)(=O)=O)c1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(NC(=O)C(CC1CCCCC1)NC(=NS(C)(=O)=O)c1ccccc1)C(O)c1nc2ccccc2o1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a mixture of N-(methoxy-phenyl-methylene)methansulfonamide (250 mg, 0.616 mmol) and 2-amino-3-cyclohexylpropionic acid [1-(benzoxazol-2-ylhydroxymethyl)-propyl]amide (255 mg, 0.616 mmol) in dry acetonitile (4 mL) at room temperature was added DBU (0.37 mL, 2.46 mmol), and the mixture was stirred at the same temperature overnight. After a removal of the solvent, the reaction mixture was partitioned between ethyl acetate and 1N-HCl solution, washed brine and then water. The organic extracts were dried, concentrated in vacuo, and purified by flash chromatography on silica gel (eluted with EtOAc/hexanes=3/1) to yield 250 mg of N-[1-(benzoxazol-2-yl-hydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminophenylmethyl)amino]-propionamide.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([N:13]1CCC[CH2:15][C:14]1=O)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:9]([O:8][C:6]([N:13]1[CH2:14][CH2:15][C:3](=[CH2:4])[CH2:2][CH2:1]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (5.4 g, 15.05 mmol) in THF (100 mL) was added slowly butyl lithium (2M, 15.05 mmol) at −78° C. The mixture was allowed to stir for one hour and N-Boc-piperidinone (2 g, 10.03 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The THF was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate, filtered and concentrated. The compound was purified by column chromatography (30% Hexanes/EtOAc) to provide the title compound (1.96 g, 99%).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][C:16]=1[Br:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Br:27][C:16]1[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:20][C:15]=1[NH:14][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:13]
Reactant: CCOC(=O)Cc1ccc(N)c(Br)c1
Reactant: O=C(O)c1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2nccc3ccccc23)c(Br)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
In DMF (15 ml) were dissolved 1-isoquinolinecarboxylic acid (1.00 g, 5.77 mmol), ethyl 4-amino-3-bromophenylacetate (1.49 g, 5.77 mmol), HOBt (0.39 g, 2.89 mmol), and DMAP (0.14 g, 1.15 mmol). To the resulting solution was added EDC HCl (1.33 g, 6.93 mmol). After stirring at 60° C. for 5 hours, the reaction mixture was cooled to room temperature. Water was added, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane:ethyl acetate (4:1, v/v) eluate fractions, ethyl (3-bromo-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (1.64 g, 69%) was obtained as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>O1CCCC1.O>[C:31]([O:1][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:14])([CH3:15])[NH:8]2)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1ccc2c(c1COC(=O)c1ccccc1)NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
8-Hydroxymethyl-7-(2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-1, 54.2 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1.5 mL) and triethylamine (73.0 μL 0.52 mmol) and benzoyl chloride (30.0 μL, 0.26 mmol) were added thereto successively. The reaction mixture was stirred at room temperature for 24 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with ethyl acetate to give the titled compound (54.1 mg) as a colorless solid. (Yield 76%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:11]O>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: NCCCCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a suspension of 6-aminocaproic acid (3.00 g, 22.9 mmol) in anhydrous MeOH (60 mL) was introduced hydrogen chloride gas for 25 minutes, during which time the suspension became clear. The solution was then stirred at room temperature for 5 hours and MeOH was removed in vacuo. The residue was recrystallized from THF to give a white solid (3.10 g). (Yield: 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH2:13][CH2:12][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(=O)OCC>[CH:25]1([CH2:24][O:23][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10][C:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH2:27][CH2:26]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
19 mg of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 200 mg of 4-(4-bromophenyl)-4-cyclopropylmethoxy-1-phenylcyclohexanecarboxylic acid in 4 ml of degassed toluene under argon in a two-necked flask and the mixture was stirred for 10 min at room temperature. Subsequently, 65.1 mg of 4-fluorobenzeneboronic acid and 0.341 ml of a 2 M sodium carbonate solution were added and the reaction mixture was heated for 24 h at 100° C. After cooling, water and EA were added, the organic phase was separated and the aqueous phase was extracted twice with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. After purification of the residue by preparative HPLC, 20 mg of the title compound were obtained as a white lyophilizate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Br)[CH:18]=[CH2:19]>>[CH2:19]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)[CH:18]=[CH2:17]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: C=CCBr
Product: C=CCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and allylbromide, the titled compound was recovered by the procedure described in Example 1. MS m/z (relative intensity, 70 eV) 279 (M+, 74), 96 (bp), 82 (98), 68 (74), 55 (93). Rf=0.42 (MeOH, 0.08 (EtOAc).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:29]([NH2:32])(=[O:31])=[O:30])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(N)(=O)=O)s2)cc1C#N
Temperature: 90 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
Prepared using General Procedure 18: To (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) in dioxane (1 mL) was added sulfamide (30 mg, 0.3 mmol) and the mixture was heated to 90° C. After 16 h, the solvent was evaporated and the residue was purified by column chromatography. Additional purification by recrystallization from MeOH provided 15.9 mg (26%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 47. LCMS-ESI (m/z) calculated for C21H21N5O3S2: 455.1; found 456.1 [M+H]+, tR=3.33 min. 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=2.3 Hz, 1H), 8.32 (dd, J=8.9, 2.4 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.56-7.38 (m, 2H), 7.23 (d, J=9.0 Hz, 1H), 6.75 (s, 2H), 4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.87 (dd, J=16.6, 8.2 Hz, 1H), 3.42-3.26 (m, 1H), 3.07 (dt, J=16.4, 8.3 Hz, 1H), 2.61 (dtd, J=11.0, 7.9, 3.0 Hz, 1H), 2.00 (dq, J=12.7, 8.8 Hz, 1H), 1.38 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 166.64, 165.62, 161.19, 146.08, 141.36, 133.89, 133.15, 127.97, 127.51, 127.27, 125.78, 122.22, 115.57, 114.95, 102.29, 72.17, 57.67, 33.41, 30.73, 21.52. Chiral HPLC: (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide was eluted in MeOH: 98.6% ee, tR=7.63 min (Chiral Method 2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Cl:27])[C:20]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1>C1COCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Cl:27])[C:20]=2[N:21]2[CH2:26][CH2:25][N:24]([CH:30]3[CH2:31][O:28][CH2:29]3)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: O=C1COC1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(Cl)c1N1CCNCC1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: C1CCOC1
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(Cl)c1N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-amino-N-(5-chloro-4-(piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide (51 mg, 0.13 mmol) (synthesized according to a procedure similar to Example 2) in THF (4 mL) was added oxetan-3-one (14.31 mg, 11.63 μL, 0.1986 mmol) and triacetoxyborohydride (Sodium Ion (1)) (56.12 mg, 0.2648 mmol), and the mixture was stirred at rt for 4 h. The reaction mixture was partitioned between an aqueous saturated solution of NaHCO3 and ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by fractionlynx to yield 2-amino-N-(5-chloro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 447.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH2:44][CH2:45][OH:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:46][CH2:45][CH2:44][O:43][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][O:37]3)[CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.8 %

Procedure:
A solution of intermediate 95a (1.42 g, 6.15 mmol) and triphenyl phosphine (3.22 g, 12.29 mmol) in THF (50 mL), under an atmosphere of argon was treated with 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.25 mL, 9.22 mmol), followed by the dropwise addition of diethyl azodicarboxylate (1.94 mL, 12.29 mmol). The reaction mixture was then stirred at RT for 1 h. Water (0.5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in EtOAc (8 mL) and cyclohexane was added until triphenylphosphine oxide had precipitated out of solution. This was filtered and the filtrate was concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as an orange/brown oil (2.98 g, >100%). LCMS (Method 3): Rt 3.20 min, m/z 360 [MH+].