Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]O.[C:7]([O:10][CH:11]=[CH:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:9])[CH3:8]>O1CCCC1>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:9])[CH3:8]
Reactant: OCCCCO
Reactant: CC(=O)OC=CCCOC(C)=O
Solvent: C1CCOC1
Product: C=CC=C
Product: CC(=O)OCCCCOC(C)=O

Procedure:
The process for preparing tetrahydrofuran according to claim 1, wherein 1,4-butanediol is prepared by hydrogenating 1,4-diacetoxybutene, which is produced by the acetoxylation of butadiene, into 1,4-diacetoxybutane and hydrolyzing said 1,4-diacetoxybutane as the hydrogenated products in the presence of a solid acid catalyst and distilling hydrolyzates thus obtained.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[CH:26]([CH2:28][CH3:29])[CH3:27]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:26]([CH2:28][CH3:29])[CH3:27])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Reactant: CCC(C)Br
Product: CCCCN1CCN(CCNC(=O)c2nn(C(C)CC)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-[2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and 2-bromobutane according to the same process as in Example 12.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH3:6][C:7]1[S:8][C:9]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1
Reactant: Cc1nc(-c2ccccc2)cs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc(C)nc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
Add n-butyllithium (0.46 mL, 0.74 mmol, 1.6 M in tetrahydrofuran) to a solution of 2-methyl-4-phenylthiazole (0.13 g, 0.74 mmol) in tetrahydrofuran (7 mL) cooled to −78° C. under a nitrogen atmosphere. Stir at −78° C. for 45 minutes, add tributyltin chloride (0.2 mL, 0.74 mmol), and stir for 2 hours as the reaction mixture warms to room temperature. Add aqueous ammonium chloride and then partition the mixture between ethyl acetate and water. Extract the aqueous phase with ethyl acetate. Wash the combined organic layers sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 10% ethyl acetate to provide the desired compound in 68% yield. MS(ES+): m/z=466.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16](Br)[CH:17]=[CH2:18].O.CN1C(=O)[CH2:25][CH2:24][CH2:23]1>>[CH2:16]([N:1]([C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[CH2:25][CH:24]=[CH2:23])[CH:17]=[CH2:18]
Reactant: Nc1cccc(O)c1
Reactant: C=CCBr
Reactant: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(CC=C)c1cccc(O)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To 3-Aminophenol (10.0 g, 0.092 mol), dissolved, in a flask, in NMP (150 ml), were added 60 ml of triethylamine and 19 ml of allyl bromide. The mixture was stirred under nitrogen at 80° C. Over a 48 hour period, an additional 22 ml of triethyl amine and 9 ml of allyl bromide were added to the flask. After cooling to room temperature, the reaction mixture was poured into 500 ml of distilled water, extracted with diethyl ether, washed with distilled water, dried over magnesium sulfate, filtered and concentrated to yield 13.5 g of 3-(N,N-diallylamino)phenol, as a red oil. Flash chromatography (silica gel, 30:70 THF:hexane) yielded 11.3 g of 3-(N,N-diallylamino)phenol as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:40][CH2:41][CH3:42])([C:6]([F:39])([F:38])[C:7]1([O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)O)=[O:5])[CH3:2].S(Cl)([Cl:45])=O>ClCCl.CN(C)C=O.CCOCC>[CH2:1]([O:3][P:4]([O:40][CH2:41][CH3:42])([C:6]([F:39])([F:38])[C:7]1([Cl:45])[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOP(=O)(OCC)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)C1(Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 14.4 g of 1-deoxy-1-(diethoxyphosphinyl)-1,1-difluoro-3,4,6-tris-O-(phenylmethyl)-D-fructofuranose in 50 ml of dichloromethane was added 7.3 ml of thionyl chloride and several drops of dimethylformamide. The solution was stirred at 25° C. for 16 hours, then diluted with ether and treated with icewater. The ether layer was washed with sodium bicarbonate solution, water and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, giving the desired compound as an oil, CMR δ 105.1 (multiplet, anomeric carbon atom).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH2:22])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][CH3:22])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(CC)cc1)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCc1ccc(CN2Cc3cc(CC)cc(Cl)c3C2=O)cc1
Yield: 49.4 %

Procedure:
A mixture of 7-chloro-5-ethenyl-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.062 g, 0.2 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.031 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.23 (t, 6H), 2.68 (q, 4H), 4.18 (s, 2H), 4.72 (s, 2H), 7.07 (s, 1H), 7.14-7.36 (m, 5H). GC-MS: m/z 313 (M)+, 284 (M−29)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]2([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:3][C:2]1=O.[CH3:21][NH2:22]>>[CH3:21][N:22]1[CH2:6][CH2:5][C:4]2([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:3][C:2]1=[O:1]
Reactant: O=C1CC2(CCO1)c1ccccc1Oc1ccccc12
Reactant: CN
Product: CN1CCC2(CC1=O)c1ccccc1Oc1ccccc12

Procedure:
A mixture of xanthene-9-spiro-4'-tetrahydropyran-2'-one (0.5 g.) and methylamine (5 ml.) is heated at 250° C. for 4 hours in a steel bomb. The gummy residue (0.52 g.) is chromatographed on silica gel, eluting with increasing concentrations of chloroform in light petroleum (b.p. 60°-80° C.). Elution with 25% chloroform in light petroleum gives, on evaporation of the solvent, a solid residue which is recrystallised from ethanol to give 1'-methylxanthene-9-spiro-4'-piperidin-2'-one, m.p. 158°-159° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:36])[C:26]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([F:37])=[C:20](F)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][N:40]1[CH2:44][CH2:43][N:42]=[C:41]1[C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:36])[C:26]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([F:37])=[C:20]([O:51][C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([C:41]3[N:40]([CH3:39])[CH2:44][CH2:43][N:42]=3)[CH:46]=2)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(N(C)c2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)CCCC1
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1(N(C)c2c(F)c(Oc3cccc(C4=NCCN4C)c3)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile (0.87 g, 1.7 mmol) in DMSO (17 mL) was added 3-(1-methylimidazolin-2-yl)phenol (0.32 g, 1.8 mmol) and cesium carbonate (0.7 g, 2.1 mmol). The resultant mixture was stirred at 35° C. After 4 days, the mixture was cooled to ambient temperature and poured into 100 mL of water and 100 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile as a solid foam: NMR (CDCl3) 7.4-6.8 (m, 12), 5.0 (s, 2), 4.2 (q, 2), 3.9 (t, 2), 3.5 (t, 2), 3.2 (s, 3), 2.8 (s, 3), 2.4-1.7 (m, 8), 1.3 (t, 3) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2)=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>CO>[C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2)([OH:4])=[O:2]
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (0.2 g) in methanol (12 mL) -tetrahydrofuran (4 mL) was added lithium hydroxide-monohydrate (0.16 g), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.18 g).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3]C.[OH-].[Na+].[CH2:8]([P:10]([CH2:17]C(C#N)C)(=[O:16])[O:11]CCCC)[CH3:9].S(=O)(=O)(O)[OH:23]>O>[CH2:8]([P:10]([OH:11])([CH2:17][CH:2]([CH3:3])[C:1]([OH:5])=[O:23])=[O:16])[CH3:9]
Reactant: O=S(=O)(O)O
Reactant: CCCCOP(=O)(CC)CC(C)C#N
Reactant: CCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(O)CC(C)C(=O)O
Temperature: 120 °C
Yield: 95.9 %

Procedure:
A stirred apparatus is initially charged with 150 g of butanol, 65 g of water, 150 g (3.75 mol) of sodium hydroxide and 271 g (1.25 mol) of butyl ethyl(2-cyano-2-methylethyl)phosphinate (produced as in Example 9). The efficiently stirred mixture was heated to about 120° C. and reacted at that temperature for about 8 hours. Then, 250 ml of water were added and the butanol was removed from the reaction mixture by distillation. Following the addition of a further 500 ml of water, the mixture was neutralized by addition of about 184 g (1.88 mol) of concentrated sulfuric acid. The water is then distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo and the residue is recrystallized from acetone to obtain 216 g (96% of theory) of 3-(ethylhydroxyphosphinyl)-2-methylpropionic acid as a solid material.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22]Br.CS(C)=O.[OH-].[Na+]>O>[C:15]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: CCCCC(C#N)c1ccc(Sc2ccccc2)cc1
Reactant: BrCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccc(Sc2ccccc2)cc1
Yield: 101.5 %

Procedure:
To a mixture of 31 g (0.1 mole) of 2-(4-phenylthiophenyl) hexanenitrile, 22 g (0.13 mole) of dibromomethane and 100 ml of dimethyl sulfoxide is added 12 g (0.15 mole) of 50% sodium hydroxide solution dropwise with stirring. Reaction mixture is stirred at 60° for 1/2 hour and then poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 38 g of product.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])=[C:9]([CH2:20][O:21][CH3:22])[CH:8]=1.[C:23](=[O:25])=[O:24]>CCOCC.CCOCC.CCOC(C)=O.O>[CH3:22][O:21][CH2:20][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: COCc1cc(Br)ccc1N1CCCCC1C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Reaction time: 0.67 h

Procedure:
To anhydrous Et2O (130 mL) at −78° C. was added tert-butyllithium (63.79 mL; 1.50 M; 95.68 mmol) (solution in pentane) which was followed by the slow addition of a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine obtained in step 3 (12.97 g; 43.49 mmol) in anhydrous Et2O (20 mL). After 40 min, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min after which time it was diluted with Et2O/EtOAc (1:1), water (pH 4-5). The organic layers were combined, dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O and pentane, filtered off and washed with pentane to give the title compound as a beige powder. 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 3.02 (m, 1H), 2.63 (m, 1H), 1.88-1.65 (m, 4H), 1.55-1.40 (m, 2H), 0.88 (d, J=6.2 Hz, 3H). LC/MS (Method B): 264.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:21]([NH:22][S:23](=[O:26])(=[O:25])[NH2:24])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:2].[OH-].[Na+].CC(O)=O>CCO.O>[NH2:2][C:1]1[C:3]2[C:4]([O:5][CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][N:8]3[C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=[CH:20][C:21]=2[NH:22][S:23](=[O:25])(=[O:26])[N:24]=1
Reactant: CCNC(=O)N1CCCCC1COc1cccc(NS(N)(=O)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCNC(=O)N1CCCCC1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a solution of 2-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26a, 0.6 g, 1.57 mmol) in EtOH (10 mL) was added NaOH 2M (1.57 mL, 1.57 mmol) and the reaction mixture was heated at 100° C. for 2 h. The solution was then evaporated to dryness. The residue was diluted with water (7.0 mL), and 10% AcOH (3.5 mL, 3.5 mmol) was added at 0° C. to provide a white precipitate which was filtered and washed with cold water and further purified by Biotage purification system (120 g Silicycle column, DCM:THF=4:1 as eluent) to give the title compound (0.318 g, 53%). MS 382 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([NH:31][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCCCS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in dichloromethane (5 mL) was added butane-1-sulfonic acid amide (44.2 mg, 0.32 mmol), N,N-dicyclohexylcarbodiimide (67.1 mg, 322 mmol) and 4-dimethylaminopyridine (40.1 mg, 0.32 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then filtered and the filtrate was concentrated and purified by chromatography (SiO2, heptane:ethyl acetate 100:0 to 0:100) to give the title compound (17 mg, 12%) as a white solid. MS: m/e=428.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][NH2:12].[N:13]1([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:11][N:12]1[C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=[C:26]1[C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:23][CH:24]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: CN
Reactant: O=Cc1ccc(OCCCN2CCCC2)cc1
Product: Cn1c(-c2ccc(OCCCN3CCCC3)cc2)nc2ncccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-aminonicotinic acid, methylamine and 4-(3-pyrrolidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[C:4](=[O:14])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.CO.O1CCCC1.[BH4-].[Na+]>O>[OH:14][CH:4]1[C:5]2[CH:6]=[C:7]3[O:13][CH2:12][O:11][C:8]3=[CH:9][C:10]=2[C:2](=[O:1])[N:3]1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2=O)OCO4)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2O)OCO4)CC1
Reaction time: 0.42 h
Yield: 69.6 %

Procedure:
To a reaction vessel, 92 g (0.23 mol) compound XI, 250 ml methanol and 250 ml tetrahydrofuran were added while stirring, the mixture was cooled to 0˜10° C., 10 g (0.26 mol) sodium borohydride was added, the reaction was kept at 0˜10° C. for 20-30 min, 100 ml water was added, the reaction mixture was concentrated to dry under reduced pressure (at 45° C.), The residue was added 500 ml ethyl acetate and 300 ml water, and extracted, the organic layer was collected, dried over sodium sulfate, concentrated to a minor amount, 300 ml petroleum ether was added, a solid was precipitated out, filtered, the filter cake was washed wth petroleum ether, dried, and 64.7 g compound VII-1 was obtained, with yield of 70%. 1H NMR (DMSO-d6): δ 0.95-1.04 (m, 2H), 1.39 (s, 10H), 1.51 (m, 2H), 1.70 (dd, 2H, J=25.0, 12.4 Hz), 2.65 (br s, 2H), 3.23-3.30 (m, 1H), 3.54-3.61 (m, 1H), 3.90 (d, 2H, J=10.0 Hz), 5.67 (d, 1H, J=8.9 Hz), 6.12 (s, 1H), 6.13 (s, 1H), 6.50 (d, 1H, J=9.0 Hz), 7.08 (s, 1H), 7.09 (s, 1H); MS (ESI): m/z 427 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[CH3:17][C:18]([CH3:21])([O-])[CH3:19].[K+].[F:23][C:24]1[CH:25]=C(C=C[CH:31]=1)CCl>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:21][C:18]([CH2:19][O:9][CH:6]2[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:4][CH2:5]2)=[CH:17][CH:31]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C1(c2ccccc2)CCC(O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(OCc2ccc(F)cc2)CC1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
2.00 g of 4-dimethylamino-4-phenylcyclohexanol were dissolved in 20 ml of dimethylformamide; 1.13 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 1.45 g of 3-fluorobenzyl chloride were added dropwise in the course of 15 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (2.66 g) was separated on silica gel with hexane/diethyl ether (V:V=1:1). 1.02 g of [4-(4-fluorobenzyloxy)-1-phenylcyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 1.05 g of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: O1CCOCC1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([CH3:37])=[C:17]([CH2:19][CH2:20][O:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH2:24][CH2:25][CH:26]=[C:27]4[CH2:32][CH2:33][C:34]([NH2:36])=O)[N:18]=2)=[CH:10][CH:9]=1.FC(F)(F)C(O)=O>N1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]([CH3:37])=[C:17]([CH2:19][CH2:20][O:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH2:24][CH2:25][CH:26]=[C:27]4[CH2:32][CH2:33][C:34]#[N:36])[N:18]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC(N)=O)c(C)o2)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC#N)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dioxane (15 ml) solution of the compound prepared in Example 10, pyridine (363 μl) and trifluoroacetic acid (423 μl) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, water and a saturated saline in this order, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to thereby obtain the title compound (533 mg) having the following physical data.