Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[C:12]([C:19](OCC)=O)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].CS(Cl)(=O)=O.[N:32]1C=CC=CC=1>O1CCCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([C:19]#[N:32])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2c(nc1Cl)CCN(C(=O)OC(C)(C)C)C2
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ncc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step A above in 6 mL of 3:2:1 tetrahydrofuran/methanol/water was added lithium hydroxide monohydrate (0.23 g, 5.58 mmol). The mixture was allowed to stir overnight and the volatiles were removed under reduced pressure. Additional water was added, and the solution was acidified with citric acid monohydrate. The resultant precipitate was collected, washed with water, and dried in vacuo. To an ice-cold solution of this intermediate (1.0 g, 3.6 mmol) in 32 mL of pyridine was added methanesulfonyl chloride (0.41 g, 3.6 mmol) dropwise, and the resultant mixture was allowed to stir for one hour. Dry ammonia gas was bubbled into the reaction mixture for 2 minutes. The excess ammonia was then removed under reduced pressure, and the solution was cooled again in ice and treated with methanesulfonyl chloride (3.43 g, 30.0 mmol). The resultant mixture was allowed to warm to room temperature overnight. The reaction was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The product was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resultant crystalline solid was triturated with ether, and the precipitate was collected to afford the title compound as a light orange powder.
Reaction SMILES: C([O:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)(C)(C)C.C1CCC([N:25]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[OH-].[NH4+]>CN(C=O)C>[C:14]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[OH:13])[C:6]([NH2:25])=[O:5])([CH3:17])([CH3:16])[CH3:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(N)=O)ccc1O
Yield: 88.4 %

Procedure:
The compound of Example 47E (800 mg, 4.1 mmol), DCC (856 mg, 5.4 mmol), and HOBt (540 mg, 5.4 mmol) were mixed in DMF (10 mL). Ammonium hydroxide (28%, 22 mL) was added to the mixture at 0° C. The reaction was stirred over night and purified by silica gel chromatography (70% -90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5%). MS (DCI) m/z 194 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([NH:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)=[O:9])[C:5]([NH:11][CH3:12])=[N:4][C:3]=1[CH3:13]
Reactant: OC1CNC1
Reactant: CNc1nc(C)c(Br)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNc1nc(C)c(Br)cc1C(=O)N1CC(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-bromo-6-methyl-2-(methylamino)nicotinic acid (0.2 g, 0.816 mmol) in DMF (3 mL) were added azetidin-3-ol (0.119 g, 1.632 mmol), HOBt (0.154 g, 1.143 mmol), and EDC (0.235 g, 1.224 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.426 mL, 2.448 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude reaction mixture was subsequently diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated by rotary evaporation to give the title compound, which was used without further purification (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH:20]1[C:25]([CH:26]=O)=[CH:24][C:23]2[O:28][CH2:29][O:30][C:22]=2[CH:21]=1>>[O:30]1[C:22]2[CH:21]=[CH:20][C:25]([CH2:26][N:17]3[CH2:18][CH2:19][CH:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[O:8][C:7](=[O:12])[CH:6]=4)[CH2:15][CH2:16]3)=[CH:24][C:23]=2[O:28][CH2:29]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)ccc2o1
Yield: 39 %

Procedure:
According to Procedure A above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and piperonal (0.032 g, 0.216 mmol) were allowed to react to give the title compound (0.0123 g, 39%, mono-TFA salt) as an off-white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.12 (br s, 1H), 7.61 (d, J=8, 1H), 7.33 (d, J=8, 1H), 7.00 (m, 2H), 6.93 (dd, J=4, 8, 1H), 6.03 (s, 2H), 5.44 (s, 1H), 4.26 (s, 2H), 3.79-3.90 (m, 1H), 3.62-3.56 (m, 2H), 3.11-3.22 (m, 2H), 2.29-2.40 (m, 2H), 1.85-1.99 (m, 2H); MS (ESI+Q1MS) m/z 413 [M]+
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[C:11]([C:13]2([CH:16]([F:18])[F:17])[CH2:15][CH2:14]2)[CH:10]=[C:9]([Br:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[ClH:20].[CH2:21](O)[CH3:22]>>[ClH:20].[NH2:1][C@H:2]([C:7]1[CH:12]=[C:11]([C:13]2([CH:16]([F:17])[F:18])[CH2:15][CH2:14]2)[CH:10]=[C:9]([Br:19])[CH:8]=1)[CH2:3][C:4]([O:6][CH2:21][CH3:22])=[O:5]
Reactant: N[C@@H](CC(=O)O)c1cc(Br)cc(C2(C(F)F)CC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C[C@H](N)c1cc(Br)cc(C2(C(F)F)CC2)c1

Procedure:
To a solution of (S)-3-amino-3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)propanoic acid (from step A above) (225.5 mg, 0.675 mmol) in absolute ethyl alcohol (3 mL) was added absolute ethanol saturated with anhydrous HCl gas (7 mL) and the reaction mixture was heated at reflux under nitrogen for 3 h to give a colorless solution. The solvent was evaporated in vacuo to give a colorless viscous liquid. The residue was triturated with diethyl ether (10 mL) and the solvent was evaporated in vacuo to give the desired (S)-ethyl 3-amino-3-(3-bromo-5-(1-(difluoromethyl)cyclopropyl)phenyl)propanoate hydrochloride salt as a colorless foamy solid (253.0 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 362 (79BrM+H), m/z 364 (81BrM+H), m/z 384 (79BrM+Na) and m/z 386 (81BrM+Na); Calcd for C15H18BrF2NO2:362.21. The isolated solid will be used as such for the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[Na+]>C(O)C>[NH2:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCC1CN(Cc2ccccc2)CCO1
Yield: 109.5 %

Procedure:
To a solution of crude 4-benzyl-2-phthalimidomethylmorpholine (64 g) in ethanol (500 ml) was added hydrazine monohydrate (18 ml, 0.57 mol) and the mixture was heated under reflux for 2 hours. After cooling, 10% aqueous sodium hydroxide (200 ml) was added to dissolve insolubles and the ethanol was distilled off under reduced pressure. The aqueous layer was extracted with chloroform (200 ml×3), the combined organic layer was dried over potassium carbonate and the solvent was distilled off to give crude 2-aminomethyl-4-benzylmorpholine (42.97 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[S:18][C@@H:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[S:18][C@@H:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H](O)[C@@H](Sc1c(OCc2ccccc2)cccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](O)[C@@H](Sc1c(N)cccc1OCc1ccccc1)c1ccc(OC)cc1
Temperature: 22 °C
Reaction time: 3.5 h

Procedure:
To 3.91 g (8.34 mmol) of (+/−)-(2S,3S)-methyl 3-(2-(benzyloxy)-6-nitrophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoate in 45 mL of ethyl acetate was added 11.3 g (5.00 mmol) of tin(II) chloride dihydrate, and the solution was stirred at 22° C. for 3.5 hours. Water, NaHCO3, and ethyl acetate were added, and the mixture was stirred at 22° C. for 1.5 hours. The stirring was stopped, and the mixture left to stand for 16 hours. The organic layer was partially separated from the aqueous layer, and the remaining mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to give (+/−)-(2S,3S)-methyl 3-(2-amino-6-(benzyloxy)phenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoate, which was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[C:11]2[N:10]=1.COCCOC.[S:44](N)([NH2:47])(=[O:46])=[O:45]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([S:44]([NH2:47])(=[O:46])=[O:45])[CH2:28][CH2:29]3)=[C:11]2[N:10]=1
Reactant: NS(N)(=O)=O
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(F)ccc32)c1NC1CCNCC1
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(F)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Temperature: 150 °C
Yield: 88.4 %

Procedure:
180 mg of 5-(2,6-difluorophenyl)-7-fluoro-N-(piperidin-4-yl)-2-([2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine, 2 ml of DME and 41 mg of sulphamide are mixed and microwave-heated at 150° C. for 1 h. The mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/aqueous ammonia mixture (95/05/0.5 by vol.), to give 183 mg of 4-{[5-(2,6-difluorophenyl)-7-fluoro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide (yellow solid). LC-MS-DAD-ELSD: 607=(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[O:5][CH2:6][C:7](Cl)=[O:8].COC1C=CC([N+]([O-])=O)=CC=1OCC(O)=O.S(Cl)(Cl)=O.[CH:37]1([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:44]1([N:43]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: COc1ccc([N+](=O)[O-])cc1OCC(=O)Cl
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: COc1ccc([N+](=O)[O-])cc1OCC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccc([N+](=O)[O-])cc1OCC(=O)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A solution of 2-methoxy-5-nitro-phenoxyacetyl chloride (0.22 g, 0.9 mmol), prepared from 2-methoxy-5-nitro-phenoxyacetic acid (Brown et al., J. Chem. Soc. 1955, 3681) and thionyl chloride, in dichloromethane (10 mL) was added to a mixture of dicyclohexylamine (0.16 g, 0.9 mmol) and diisopropylethylamine (0.23 g, 1.76 mmol) in dichloromethane (20 mL), maintained at RT for 16 h, washed with water (2×20 mL), dried (Na2SO4), and concentrated in vacuo. The residue was recrystallized from methanol to afford the title compound (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]1[C:14](=[O:15])[C:13]2([CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[N:12]([CH3:23])[C:11]1=[O:24].C(=O)([O-])O.[Na+].S(Cl)([Cl:33])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:33][C:10]1([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])[C:14](=[O:15])[C:13]2([CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: CON1CCC2(CC1)C(=O)C(c1cc(C)c(C)cc1Cl)C(=O)N2C
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CON1CCC2(CC1)C(=O)C(Cl)(c1cc(C)c(C)cc1Cl)C(=O)N2C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(2-chloro-4,5-dimethyl-phenyl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (compound P2.26) (120 mg, 0.342 mmol) and sodium hydrogen carbonate (72 mg, 0.857 mmol) in dichloromethane (5 ml) at −5° C. was added sulfuryl chloride (0.026 ml, 43.3 mg, 0.321 mmol) in dichloromethane (0.5 ml) dropwise. The reaction mixture was stirred at 0° C. for 1.5 hour, poured on saturated aqueous sodium carbonate, the layers were separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate). Yield: 120 mg of 3-chloro-3-(2-chloro-4,5-dimethyl-phenyl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.1) as a white solid, mp 93-94° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>C(Cl)Cl.CO.[NH4+].[Cl-]>[Cl:3][C:4]1[N:5]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[C:6]2[C:11]([C:12]=1[CH2:13][OH:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: N#Cc1ccccc1-n1c(Cl)c(C=O)c2ccccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccccc1-n1c(Cl)c(CO)c2ccccc21
Yield: 100.1 %

Procedure:
NaBH4 (6 mg, 159 μmol, Eq: 0.387) was added to a solution of 2-(2-chloro-3-formyl-1H-indol-1-yl)benzonitrile (115 mg, 410 μmol, Eq: 1.00) in DCM (3 mL) and MeOH (3.00 mL) at 0° C. and the mixture brought to RT. After 2 h 15 min. the mixture was diluted with sat. NH4Cl and extracted with DCM and the extracts concentrated to afford the title compound (116 mg, 100%) which was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCO.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.O>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=Cc1cc(Br)ccc1F
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: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=Cc1cc(-c2cccc(F)c2)ccc1F
Temperature: 100 °C
Yield: 34.1 %

Procedure:
To a stirred mixture of 5-bromo-2-fluoro-benzaldehyde (3.0 g, 14.8 mmol, 1 eq), (3-fluorophenyl)boronic acid (2.48 g, 17.7 mmol, 1.2 eq) and K2CO3 (4.13 g, 44.4 mmol, 3 eq) in a mixture of EtOH (30 mL), DMF (30 mL) and water (10 mL) under N2 was added Pd(PPh3)4 (1.71 g, 1.48 mmol, 0.1 eq). The reaction was heated at 100° C. for 3 h, then filtered through Celite. The filtrate was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 300:1) to give the title compound as a yellow oil (1.1 g, 34%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1>Cl.O1CCOCC1>[NH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2nc3ccccc3s2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2sc(CC3CCCNC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
0.58 g (1.75 mmol) of tert-butyl 3-benzothiazol-2-ylmethylpiperidine-1-carboxylate were dissolved in 5.0 ml of hydrogen chloride/dioxane (4 N) and stirred at room temperature for 1 h. The solvent was removed in vacuo, and the residue was dissolved in 50 ml of water. The aqueous phase was adjusted to pH=9 using sodium hydroxide solution (1 N) and extracted with 2×50 ml of ethyl acetate. Conventional work-up gave 0.41 g of 2-piperidin-3-ylmethylbenzothiazole; HPLC/MS (M+H)+=233 as oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1.[CH3:15][NH:16][C:17]([C:19]1[C:23]2[CH:24]=[C:25]([O:33][CH:34]([CH3:36])[CH3:35])[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:22]=2[O:21][C:20]=1[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:18].[I-].[K+]>C(#N)C>[CH3:15][NH:16][C:17]([C:19]1[C:23]2[CH:24]=[C:25]([O:33][CH:34]([CH3:36])[CH3:35])[C:26]([N:28]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:9][C:10]3[N:11]=[CH:12][S:13][CH:14]=3)=[CH:27][C:22]=2[O:21][C:20]=1[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:18]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Reactant: ClCc1cscn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3cscn3)S(C)(=O)=O)c(OC(C)C)cc12
Temperature: 25 °C
Yield: 48 %

Procedure:
Potassium carbonate (0.050 g, 0.357 mmol) followed by 4-(chloromethyl)thiazole hydrochloride (0.041 g, 0.238 mmol) were added to a solution of 2-(4-fluoro-phenyl)-5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (0.050 g, 0.119 mmol, which can be prepared according to one of the procedures described in Example 21 above), dissolved in acetonitrile (10 mL). The reaction was refluxed for 1 hour with no visible product formation observed by TLC, so potassium iodide (0.020 g, 0.120 mmol) was added to the reaction. The mixture was refluxed for an additional 2 hours, and then cooled to room temperature. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and washed with water. The product was concentrated and purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to provide 30 mg (48%) of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[S:23][CH:24]=2)[CH2:15][CH2:14]1)([O-])=O.C(O)C.[Cl-].[NH4+]>O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[S:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccc([N+](=O)[O-])cc34)CC2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccc(N)cc34)CC2)cs1
Temperature: 80 °C
Yield: 71.4 %

Procedure:
A mixture of 4-[4-(5-nitro-3-indolyl)piperidinomethyl]-2-propionylaminothiazole (1.39 g) and ethanol (60 ml) was added to a solution of ammonium chloride (1.08 g) in water (20 ml), followed by stirring at 80° C. Iron (1.13 g) was added thereto and the mixture was refluxed for 2 hours, after which it was filtered. The residue was washed with hot ethanol and the filtrate and washings were combined and concentrated under reduced pressure. The residue was made alkaline to litmus paper with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol to give 4-[4-(5-amino-3-indolyl)piperidinomethyl]-2-propionylaminothiazole (0.92 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)O.CC(C)=[O:19]>O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]1[C:12](=[O:19])[CH:16]=[CH:15][CH:14]1[OH:13]
Reactant: Cc1cc(C)c(C(O)c2ccco2)c(C)c1
Reactant: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(C2C(=O)C=CC2O)c(C)c1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
A solution of (2,4,6-trimethylphenyl)furan-2-ylmethanol (27.8 g, 129 mmol) in acetone (730 ml) and water (100 ml) is heated to 55° C. and polyphosphoric acid (2 g) is added. The mixture is stirred at 55° C. for 7 hours, then cooled to room temperature overnight. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (500 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(2,4,6-trimethylphenyl)-4-hydroxycyclopent-2-enone.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C.CC#N>[Br:1][C:2]1[C:3]([F:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[C:5]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1)=[O:7]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1c(Cl)ccc(Br)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(NC(=O)c2c(Cl)ccc(Br)c2F)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorobenzoic acid (1 g, 3.95 mmol) in DCM (20 mL) was added DMF (1 drop) followed by oxalyl chloride (0.7 mL, 7.89 mmol) dropwise. The reaction was stirred at room temperature for 30 minutes before concentrating in vacuo and azeotroping with DCM. The residue was dissolved in MeCN (5 mL) and 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (655 mg, 3.56 mmol) and triethylamine (0.55 mL, 3.95 mmol) in MeCN (7 mL) were added. The reaction was heated at 120° C. for 1 hour under microwave irradiation. 2M NaOH (aq) (20 mL) was added with vigorous stirring at room temperature for 1.5 hours. The organic layer was separated, washed with 2M HCl (aq) (2×20 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10-30% EtOAc in heptanes to afford the title compound (200 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]1([F:35])[CH2:34][O:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2([F:35])[CH2:34][O:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: FC1(CBr)COC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC4(F)COC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 3-bromomethyl-3-fluoro-oxetane (described in US2005215599) gave the title compound. ES-MS m/e (%): 487.1 (M+H+).