Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C@H:13]([OH:17])[C:14]([OH:16])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:21][C@H:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][C:26]([OH:32])=[CH:27][CH:28]=2)[CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:13]([OH:17])[C:14]([NH:21][C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][C:26]([OH:32])=[CH:27][CH:28]=3)[CH2:23]2)=[O:16])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Reactant: O=C(O)[C@@H](O)c1ccc(OCc2ccccc2)cc1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1ccc(OCc2ccccc2)cc1
Yield: 93.9 %

Procedure:
(S)-4-Benzyloxymandelic acid (1.80 g), (S)-2-amino-7-hydroxytetralin hydrobromide (1.87 g) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (3.39 g) were dissolved in N,N-dimethylformamide (21 ml), and triethylamine (2.03 ml) was added to the solution under ice-cooling with stirring. After reaction at room temperature for an hour, diethyl ether and water were added to the reaction mixture. Collection by filtration of the resulting precipitates gave (2S)-2-(4-benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (2.64 g) as powders.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]3[C:6]=2[C:5]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)cccc2N(N)CC1
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 13.7 %

Procedure:
To a solution of 7-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.20 g, 5.32 mmole) in 1-propanol (100 mL) was added cyclopentanone (6.66 g, 79.14 mmole) followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole) and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.20 g of the title compound as a white solid, mp 138-140° C.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:19]=[C:18]([C:20]4[NH:21][C:22]([C:25]5[O:26][C@@H:27]([CH3:30])[CH2:28][N:29]=5)=[CH:23][CH:24]=4)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34]C)[CH:15]=3)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[Cl-].[NH4+]>ClCCl>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([C:20]4[NH:21][C:22]([C:25]5[O:26][C@@H:27]([CH3:30])[CH2:28][N:29]=5)=[CH:23][CH:24]=4)[CH:19]=3)[O:31][C@@H:32]([CH3:36])[CH2:33][OH:34])=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ncc(C(=O)N5CCC5)cc4Cl)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
5-(azetidin-1-ylcarbonyl)-3-chloro-2-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine (320 mg, 0.610 mmol) synthesized in Example 74 was dissolved in dichloromethane (10 mL), and boron tribromide (1.0 mol/L dichloromethane solution, 0.92 mL, 0.92 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with dichloromethane (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=1%-3%) to afford the desired compound (165 mg, yield 53%) as a yellow solid.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH:14]([OH:17])([CH3:16])[CH3:15].[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35](O)=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)Cl>[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35]([O:17][CH:14]([CH3:16])[CH3:15])=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12
Reactant: CC(C)O
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
7.1 ml of tri-n-butylamine and 6.1 ml of isopropanol were added to a suspension of 2.0 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2.3-a]quinolizine-10-carboxylic acid and 3.8 g of N-methyl-2-chloropyridinium iodide in 12.5 ml of methylene chloride, the reaction mixture was stirred under reflux for 24 hours, evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). After crystallization from methanol, there was obtained pure isopropyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 165.5°-166°.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:36])=[C:18]([C:20]2[C:21](=[O:35])[NH:22][C:23]3([C:33]=2[OH:34])[CH2:32][CH2:31][C:26]2(OCC[O:27]2)[CH2:25][CH2:24]3)[CH:19]=1>CC(C)=O.O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:36])=[C:18]([C:20]2[C:21](=[O:35])[NH:22][C:23]3([CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32]3)[C:33]=2[OH:34])[CH:19]=1
Reactant: Cc1ccc(Br)cc1C1=C(O)C2(CCC3(CC2)OCCO3)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCC(=O)CC2)NC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
192 mg (1.01 mmol) of 4-toluenesulphonic acid monohydrate were added to 2.49 g (6.32 mmol) of 11-(5-bromo-2-methylphenyl)-12-hydroxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-en-10-one (Example 38A) in 26 ml of acetone and 13 ml of water. The reaction mixture was stirred at 80° C. overnight. For work-up, the cold reaction mixture was diluted with water and acetone was removed on a rotary evaporator. The precipitated crude product was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. Drying gave 1.97 g (89% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:18])=[C:13]([F:30])[CH:12]=1>>[F:30][C:13]1[C:12]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:16]=[CH:15][C:14]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:18]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cccnc1
Product: O=C(c1cccc(-c2ccncc2)c1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure FF starting from 3-pyridine boronic acid and (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 354.2
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:30]
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)ccc1OCC=C(C)C
Yield: 70 %

Procedure:
In a manner identical to Example 15, 2,5-diprenyloxybenzoic acid(1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.40 g(70%) of the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([S:7][CH2:8][C:9]([O:11]C)=[O:10])=[CH:5][CH:6]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:3][C:4]([S:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: COC(=O)CSc1ccc(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(SCC(=O)O)o1
Yield: 58.7 %

Procedure:
This ester (18.6 g) was heated under reflux in ethanol (50 ml) containing 2 M aqueous sodium hydroxide (50 ml) for one hour. The solvent was evaporated. The residual mixture was diluted with ice-water (300 ml) and extracted with ether (3×20 ml). The ice-cold aqueous layer was acidified to pH 1 with 6 M hydrochloric acid and extracted with ether (3×300 ml). These extracts were dried (MgSO4) and evaporated to leave an oil which was recrystallised from petrol 60°-80° C. to give 2-(2-methylfur-5-ylthio)acetic acid, (10.1 g) m.p. 35°-36° C.; NMR (90 MHz): 2.35 (s,3H), 3.50 (s,2H), 6.00 (m,1H), 6.55 (d,1H), 11.27 (br,s).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Br[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][C:46]([CH3:51])([CH3:50])[CH2:45]1)=O>>[CH3:50][C:46]1([CH3:51])[CH2:47][CH2:48][CH2:49][N:44]([CH2:42][CH2:41][O:10][C:8]2[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:35][CH:34]=2)[CH2:45]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Product: COc1cc(NCCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 20.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][C:16]2[C:21]([Br:22])=[CH:20][CH:19]=[C:18](Br)[C:17]=2[F:24])[CH:14]=1)[C:10]#[N:11].CN([CH:28]=[O:29])C>C1COCC1.C1(C)C=CC=CC=1>[Br:22][C:21]1[C:16]([O:15][C:13]2[CH:12]=[C:9]([CH:8]=[C:7]([Cl:6])[CH:14]=2)[C:10]#[N:11])=[C:17]([F:24])[C:18]([CH:28]=[O:29])=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Br)c2F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(C=O)c2F)c1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A solution of i-PrMgCl (17.3 mL of a 2 M solution in THF, 1.75 equiv) was added slowly to a solution of the 103 (8.0 g, 19.7 mmol) in toluene (160 mL) at −78 C. The solution was aged for 1.5 h then transferred by cannula to a flask containing DMF (2.3 mL, 1.5 equiv) in toluene (30 mL). The solution was quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was separated, washed with brine, dried, and evaporated. The crude product was purified by SiO2 by chromatography eluting with 20% EtOAc/hexanes to afford 6.5 g (98%) of 3-(6-bromo-2-fluoro-3-formyl-phenoxy)-5-chloro-benzonitrile (105) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([NH2:20])=S)[CH2:3][CH2:2]1.[OH-].[K+].[CH3:23][NH:24][CH3:25].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH3:23][N:24]([CH3:25])[C:18]([NH2:20])=[N:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NC(=S)Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)C(N)=Nc1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
A mixture of 1-(2-morpholino-5-trifluoromethylphenyl)thiourea (6.1 g), potassium hydroxide (2.2 g), a 33% ethanolic solution of dimethylamine (5.6 ml), lead acetate trihydrate (7.5 g) and ethanol (40 ml) was heated at 90°-95° C. for 2 hours to yield 1,1-dimethyl-2-(2-morpholino-5-trifluoromethylphenyl)guanidine (m.p. 132°-135° C.) which was recrystallised from ethylacetate and converted into its fumaric salt (m.p. 228°-230° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Br:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34]N>>[Br:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(F)cc1Br
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1Br

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2-bromo-4-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=496.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc(OC)c1
Temperature: 25 °C

Procedure:
After 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added and, the ethyl acetate phase was washed with 2N-hydrochloric acid 50 ml twice and with saturated sodium bicarbonate solution 50 ml. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 388.5 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([N:24]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])[CH3:25])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.O.O.[OH-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([N:24]([C@@H:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])[CH3:25])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.8 %

Procedure:
(S)-methyl 2-(3-(4-(3-(2-fluorophenyl)ureido)phenyl)-N-methylisoxazole-5-carboxamido)-3-methylbutanoate (80 mg, 0.17 mmol) was dissolved in THF and water in 2:1 ratio. Lithium hydroxide monohydrate (14 mg, 0.341 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to yield 30 mg (39%) of the title compound. MS: ES (−): m/z 453 (M−1); ES (+): m/z 455(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.427(s, 1H), 8.713 (d, 1H), 8.171 (m, 1H), 7.905-7.851 (d, 2H), 7.677-7.524 (m, 3H), 7.283 (m, 1H), 7.183 (t, 1H), 7.068 (m, 1H), 4.661-3.949 (d, 1H), 3.161-2.977 (s, 3H), 2.314 (m, 1H), 1.335-1.065 (d, 3H(×2)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.30 g, 1.1 mmol), benzyl bromide (0.61 g, 3.5 mmol) and potassium carbonate (0.32 g, 2.3 mmol) and DMF (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.39 g, 95%).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:7]=1[CH3:8].Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:16][CH:2]([F:1])[C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[C:7]=1[CH3:8]
Reactant: ClCCN1CCCCC1
Reactant: Cc1c(C(F)F)cnn1-c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(F)F)cnn1-c1ccc(OCCN2CCCCC2)cc1
Yield: 55.6 %

Procedure:
A mixture of 4-(4-Difluoromethyl-5-methyl-pyrazol-1-yl)-phenol (30 mg, 0.134 mmol), 1-(2-chloroethyl)piperidine hydrochloride (50 mg, 0.27 mmol), K2CO3 (55 mg, 0.4 mmol), in DMF (1 mL) was stirred at 90° C. for 18 h. After the reaction mixture was quenched with water, the reaction mixture was extracted with CH2Cl2, washed 10% NaOH, and brine, dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel eluting with 20% ethyl acetate/hexane to yield the title compound (25 mg, 56%); 1H NMR (400 MHz, CDCl3) 7.70 (br s, 1H), 7.30 (d, J=13.2 Hz, 1H), 7.00 (d, J=13.2 Hz, 2H), 6.71 (t, J=96, 52 Hz, 1H), 4.16 (t, J=12, 6 Hz, 2H), 2.65 (t, J=12, 6 Hz, 2H), 2.53 (br, 4H), 2.34 (s, 3H), 1.61-1.47 (m, 6H); LC/MS (ESI) m/z: 336 (M+1, 100), 97%.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[NH2:33][N:34]([CH2:42][CH3:43])C(=O)OC(C)(C)C>C(O)C>[ClH:32].[CH2:42]([N:34]1[C:6]2[C:7]3[CH:8]=[C:9]([F:27])[CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:5]=2[CH:4]=[N:33]1)[CH3:43]
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCn1ncc2c1-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.3 g, 3.0 mmol) in ethanol (10.4 mL) was added hydrochloric acid (11.1 mL of 4 M, 44.6 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-ethyl-carbamate (571.2 mg, 3.6 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (3.7 mL of 4 M in dioxane, 14.9 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly, cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of EtOH in hexanes (2×). Residual solvent was further removed under reduced pressure providing 1-ethyl-8-fluoro-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (880 mg, 82%). ESI-MS m/z calc. 287.1. found 288.1 (M+1)+. Retention time 0.79 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=9.4, 2.8 Hz, 1H), 7.47 (s, 1H), 7.26-7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.30-3.12 (m, 4H), 2.18-2.01 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>C(OCC)C.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][O:23][C@@H:15]1[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: OCc1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 81.8 %

Procedure:
To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran in 25 ml of diethyl ether were added 1.06 g of 2,4-dichlorobenzyl alcohol, followed by a catalytic amount (2-3 drops) of phosphorus oxytrichloride. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added to the mixture, which was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel as in Example 1(a), to give 1.82 g of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the lesser polarity), 144 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the greater polarity) and 200 mg of a cis/trans mixture.