Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:30]=[CH:29][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].C(O)C.Cl.[NH2:35][OH:36].C(N(CC)CC)C>O>[OH:36][NH:35][C:25](=[NH:26])[C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[CH:29]=[CH:30][C:10]([C:5]3[N:6]=[C:7]([CH3:9])[S:8][C:4]=3[CH:1]([CH3:2])[CH3:3])=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: NO
Reactant: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(C(C)C)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(OCCCCCOc3ccc(C(=N)NO)cc3)cc2)c(C(C)C)s1
Reaction time: 15 h
Yield: 91.1 %

Procedure:
While 45 g of 4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzonitrile (10) prepared in Example 6 were added to 300 ml of ethanol and stirred, 15 g of hydroxylamine hydrochloride and 30 ml of triethylamine were added. The temperature was gradually increased and stirring under reflux was continued for 15 hr. After the reaction was completed, the temperature was decreased to 40° C., and the resultant reaction solution was slowly added with water, thereby being crystallized. The precipitated solid was filtered and washed with water, thus obtaining 44.2 g (yield: 95%) of a title compound as a white solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([CH2:31][N:32]([CH3:34])[CH3:33])[CH2:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([CH2:31][N:32]([CH3:34])[CH3:33])[CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:11][CH2:10]1
Reactant: CN(C)CC(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CC(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4N hydrogen chloride in ethyl acetate (1 ml; 4 mmol) was added to a solution in ethyl acetate (0.5 ml) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-[(dimethylamino)methyl]propane (92 mg; 0.20 mmol) synthesized by the process described in Referential Example 5, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 1,3-bis(4-piperidinyl)-2-[(dimethylamino)methyl]propane trihydrochoride.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[O:20]1[CH2:27][CH:21]1[CH2:22][NH:23][CH:24]([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)C.C(OC(C)C)(C)C>[OH:20][CH:21]([CH2:22][NH:23][CH:24]([CH3:26])[CH3:25])[CH2:27][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Reactant: CC(C)NCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)NCC(O)COC1c2ccccc2C(=O)N1c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 13.2 %

Procedure:
A solution of 3-hydroxy-2-phenyl-isoindolin-1-one (6.75 g.) in anhydrous dimethylformamide (20 cc.) is added to a suspension of sodium hydride (50% dispersion in mineral oil) (1.48 g.) in anhydrous dimethylformamide (20 cc.). When the evolution of gas has ceased, 2,3-epoxy-1-isopropylamino-propane (3.8 g.) is added whilst keeping the temperature at about 5° C. After the end of the addition, stirring is continued for a further 24 hours at a temperature of about 20° C. and then the reaction mixture is poured into ice-water (250 cc.). The insoluble oily product is extracted with methylene chloride (3 × 100 cc.). The solution obtained is dried over sodium sulphate and then concentrated to dryness under reduced pressure. The oily residue is taken up in diethyl ether (50 cc.) and the insoluble product is filtered off and then washed with diethyl ether (30 cc.). The filtrate is then extracted with 0.5N hydrochloric acid (60 cc.). The acid solution obtained is washed with diethyl ether (20 cc.) and then rendered alkaline by the addition of 1N sodium hydroxide solution (30 cc.). The insoluble oily product is extracted with diethyl ether (2 × 50 cc.) and the solution obtained is dried over sodium sulphate and then concentrated to dryness under reduced pressure. The oily product obtained is dissolved in a mixture of diethyl ether and di-isopropyl ether (1/1 by volume; 20 cc.), and the product which crystallises is filtered off and then washed with a mixture of diethyl ether and di-isopropyl ether (1/1 by volume; 5 cc.). After drying, 3-(2-hydroxy-3-isopropylamino-propoxy)-2-phenyl-isoindolin-1-one (1.35 g.), melting at 92° C., is obtained.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]1([C:28]2[S:29][CH:30]=[C:31]([CH2:33]O)[N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][CH2:33][C:31]1[N:32]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:29][CH:30]=1
Reactant: BrBr
Reactant: OCc1csc(-c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1csc(-c2ccccc2)n1
Temperature: -6 °C
Yield: 93.8 %

Procedure:
Bromine (177 mg, 1.1 mmol) was added directly into a solution of triphenylphosphine (288 mg, 1.1 mmol) in DCM (2 mL) to give a kind of white precipitate. The temperature was cooled to −6° C. A solution of commercially available (2-phenylthiazol-4-yl)methanol (200 mg, 1.04 mmol) in DCM (1 mL) was added dropwise. The resulting mixture was maintained at −6° C. for 15 min and then warmed to room temperature for 1h. A white precipitate was formed. The solution was filtered and the white precipitate was washed with DCM. The white precipitate was collected and dissolved in NaHCO3 0.5M After 30 min of stirring, the aqueous layer was extracted with DCM and the organic phase was washed with water, dried over MgSO4, filtered and evaporated to afford 248 mg of 4-(bromomethyl)-2-phenylthiazole (Yield 71%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([F:26])=[CH:20][C:21]=4[F:25])[N:16]([CH2:27]CC#N)[C:15]=3[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:31].[Na+].[CH2:33]([OH:35])[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([F:26])=[CH:20][C:21]=4[F:25])[N:16]([CH2:27][CH2:34][C:33]([OH:31])=[O:35])[C:15]=3[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#CCCn1c2c(c3c(F)cc(F)cc31)CC(NS(=O)(=O)c1ccc(Cl)cc1)CC2
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCn1c2c(c3c(F)cc(F)cc31)CC(NS(=O)(=O)c1ccc(Cl)cc1)CC2

Procedure:
3.05 g (6.8 mmol) of the compound from Example III are dissolved in 20 ml of ethanol, 100 ml of 10% strength sodium hydroxide solution are added, and the mixture is then stirred under reflux for 16 hours. The cooled batch is extracted by shaking twice using 50 ml of methylene chloride each time, and a pH of 1 is established at 0° C., using 6 N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water to neutrality, dried in a high vacuum over phosphorus pentoxide and sodium hydroxide, and weighed.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([CH:35]=[C:34]([O:36][CH3:37])[CH:33]=1)[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1cc(CNC(=O)C(C)C(=O)O)cc(OC)c1
Product: COc1cc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc(OC)c1

Procedure:
The title compound, MS: m/e=515.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3,5-dimethoxy-benzyl)-malonamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:20])[C:9]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][O:24][C:25](Cl)=[O:26]>N1C=CC=CC=1>[Cl:21][CH2:22][CH2:23][O:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:20])[C:9]([NH:11][C:12]2[N:13]([C:25]([O:24][CH2:23][CH2:22][Cl:21])=[O:26])[N:14]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[CH:16]=2)=[O:10])=[CH:6][CH:7]=1)=[O:26]
Reactant: O=C(Cl)OCCCl
Reactant: CC(C(=O)Nc1cc(C2CC2)[nH]n1)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OCCCl)c1ccc(NC(=O)OCCCl)cc1
Yield: 81.7 %

Procedure:
154 mg (0.57 mmol) of 2-(4-aminophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide were dissolved in 1.9 ml of dry pyridine at 4° C. under argon atmosphere and 0.12 ml (1.148 mmol) of 2-chloroethylchloroformate were added dropwise. After 2.5 hours the reaction mixture was poured into ice and the precipitate solid collected by filtration, affording 225 mg (82% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[N:21]=[C:20]([CH2:27][CH3:28])[CH:19]=1>C(O)C>[C:9]([CH:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]2[N:23]3[N:24]=[CH:25][CH:26]=[C:22]3[N:21]=[C:20]([CH2:27][CH3:28])[CH:19]=2)=[CH:7][CH:6]=1)#[N:10]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: N#CC(c1ccccc1)c1ccc(N)cc1
Solvent: CCO
Product: CCc1cc(Nc2ccc(C(C#N)c3ccccc3)cc2)n2nccc2n1
Temperature: 25 °C

Procedure:
2.1 g (10.1 mmol) 2-(4-Aminophenyl)-2-phenylacetonitrile (prepared by catalytic hydrogenation of phenylcyanomethylenequinone oxime according to the method of R. B. Davis, D. D. Carlos, G. S. Mattingly, J. Org. Chem. 1965, 30, 2607) and 1.8 g (9.9 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) were dissolved in 50 ml dry ethanol and heated with reflux for 10 h. Solid materials, which precipitated after cooling to room temperature, were filtered, the filtrate evaporated in vacuo, the residue treated with 10% aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo to afford the crude title compound as an oil, which was pure enough for the next step as detected by its 1H-NMR spectrum.
Reaction SMILES: C([S:4][C:5]([CH3:11])([CH3:10])[CH2:6][C:7](=[O:9])[CH3:8])(=O)C.[BH4-].[Na+].[O:14]([CH3:16])[Na].[CH3:17]O>O>[C:16]([O:9][CH:7]([CH2:6][C:5]([SH:4])([CH3:10])[CH3:11])[CH3:8])(=[O:14])[CH3:17]
Reactant: CO
Reactant: CC(=O)CC(C)(C)SC(C)=O
Reactant: CO[Na]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(C)CC(C)(C)S
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
4-Acetylthio-4-methylpentan-2-one (17 g, prepared as described by R. Brown, W. E. Jones and A. R. Pinder, J. Chem. Soc. 1951, 2123), was dissolved in 25 ml of methanol. A solution of 1.945 g of NaBH4 and of 0.1 g of NaOCH3 in 25 ml of methanol was added dropwise through a dropping funnel, keeping the temperature of the reaction mixture between 10° and 25° C. by occasionally cooling with ice water. After standing overnight the reaction mixture was diluted with a same volume of water and extracted twice with n-pentane. The pentane extract was washed neutral with an aqueous solution of sodium chloride, dried over sodium sulphate and concentrated. Distillation of the residue yielded 19 g (52.5%) of 4-mercapto-4-methylpent-2-yl acetate, b.p. 37°-39° C./1 mm, nD20 1.4530.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH2:27]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:28]>CCCCCCC>[CH3:17][C:14]([CH3:15])([CH3:16])[CH2:13][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:33]([C:32]3[CH:34]=[CH:35][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=[O:18]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)CC(C)(C)C)CC1
Reactant: CCc1ccc(N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCc1ccc(N2CCC3(CCN(C(=O)CC(C)(C)C)CC3)C2=O)cc1
Yield: 69.2 %

Procedure:
This material was prepared in analogy to example 1 step D) 1-(3,3-Dimethyl-butyryl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.15 g), dimethylaluminium chloride in heptane (1.0 molar, 0.96 ml) and 4-ethylaniline (0.087 g) to give the desired 8-(3,3-dimethyl-butyryl)-2-(4-ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.118 g) as an off-white solid. MS (ESI): 357.25 (MH+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:11])([O-])[O-:9].[K+].[K+].[Br:14][C:15]1[CH:16]=[C:17]([C:23](OC)=O)[C:18](CBr)=[CH:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:8]([OH:9])=[O:11])=[C:17]([CH2:23][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Br)cc1COc1ccccc1
Yield: 65.1 %

Procedure:
Phenol (8 g, 85 mmole) and potassium carbonate (11.7 g, 85 mmole) in 150 mL of N,N-dimethylformamide was reacted with methyl 4-bromo-α-bromo- 2-toluate (20 g, 65 mmole) by the procedure of Example 6, step a and followed with alkaline hydrolysis by the procedure of Example 6, step b to give the crude 4-bromo-2-(phenoxymethyl)benzoic acid (13 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.C(OC1C=CC(O)=CC=1C(C)(C)C)(=O)C.[C:33]([O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C>S(Cl)(Cl)=O.CCCCCC>[C:33]([O:37][C:38]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:15][C:14]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[O:16])=[CH:44][CH:45]=1)=[O:47])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Agent: CC(=O)Oc1ccc(O)cc1C(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43 mmol) in thionyl chloride (10 mL) was refluxed for 2 h. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in 5 mL of dichloromethane and treated with triethyl amine (5 mL) followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088 g, 0.427 mmol). After 0.5 h, the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound(0.1 g, 55%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([NH:16][CH3:17])=[O:15])[C:4]=2[CH:3]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[OH:32][C@@:25]1([C:23]#[C:24][C:2]2[CH:22]=[CH:21][C:5]3[O:6][CH2:7][CH2:8][C:9]4[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=4[C:14]([NH:16][CH3:17])=[O:15])[C:4]=3[CH:3]=2)[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]
Reactant: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CNC(=O)c1c(C(N)=O)nn2c1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 25 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-N3-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as a brown solid (32 mg, 25%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.O>[Si:20]([O:10][CH2:9][CH2:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCNc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCNc1ccccc1
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 2-(phenylamino)ethan-1-ol (2.0 g, 14.6 mmol) and imidazole (2.9 g, 43.7 mmol) in DCM (20 mL) was added TBSCl (2.6 g, 16.0 mmol) at r.t., and the reaction was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (PE:EtOAc=40:1) gave 3.0 g (82%) of the title compound as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1.[C:18](=O)([O-])[O-:19].[Na+].[Na+]>CN(C)C=O>[CH:18]([C:15]1[S:14][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)=[CH:17][CH:16]=1)=[O:19]
Reactant: Brc1cccc(-c2cccs2)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cccc(Br)c2)s1
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (1.15 mL; 15.4 mM) was added slowly to stirring dimethylformamide (0.95 mL; 12.2 mM) at -10° under nitrogen. The resulting mixture was stirred for 15 mins. 2-(3'-bromophenyl)thiophene (2.12 g; 9 mM) was then added. The reaction mixture was then warmed slowly to 110° over a period of 1 hr. cooled and poured into ice, and cautiously neutralized with sodium carbonate. Extraction with ethyl acetate and drying the organic phase with anhydrous magnesium sulfate provided upon concentration 2.16 g of the desired aldehyde as an oily solid.
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]2[CH:8]=[C:9]([F:13])[C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:15])[F:14].[N:17]([O-])=O.[Na+].[CH3:21][O:22][CH2:23][C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27].CC([O-])=O.[Na+]>Cl.O.CCO>[CH3:21][O:22][CH2:23][C:24](=[O:30])[C:25](=[N:17][NH:12][C:10]1[C:9]([F:13])=[CH:8][C:6]2[O:7][C:2]([F:1])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]=2[CH:11]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1cc2c(cc1F)OC(F)(F)C(F)(F)O2
Reactant: O=N[O-]
Reactant: COCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCC(=O)C(=NNc1cc2c(cc1F)OC(F)(F)C(F)(F)O2)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a suspension of 2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-amine (4.87 g, 20.2 mmol) in 6 M HCl aqueous solution (20.2 mL) was added a solution of NaNO2 (1.67 g, 24.2 mmol) in water (4 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. To a suspension of methyl 4-methoxy-3-oxobutanoate (2.61 mL, 20.2 mmol) and NaOAc (303 g) in EtOH (34 mL) was added the above solution at 0° C. The mixture was stirred at 0° C. for 15 min. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound (6.84 g, 85% yield) as a red solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.33 (3H, s), 3.82 (3H, s), 4.68 (2H, s), 7.66-7.93 (2H, m), 12.16 (1H, brs).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C@H:19]([O:21][CH2:22][C:23]3([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:29][N:26]1[CH2:25][CH2:24][C:23]([CH2:22][O:21][C@@H:19]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=2)[CH3:20])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][CH2:27]1
Reactant: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](OCC1(c2ccccc2)CCN(C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (300 mg, 0.53 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 6 mL) for 1 h. The solvent was removed in vacuo and the resulting crude product dissolved in acetonitrile (5 mL), cooled to 0° C. and treated with formaldehyde (37 wt. % solution in water, 1.1 mL). The reaction was treated with sodium cyanoborohydride (163 mg, 2.58 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 222 mg (73%). 1H-NMR (CDCl3, 300 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.21-7.35 (m, 6H), 7.09-7.14 (m, 1H), 4.27 (q, J=6.6 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 3.24 (d, J=8.8 Hz, 1H), 2.50-2.57 (m, 2H), 2.15 (s, 3H), 1.93-2.22 (m, 6H), 1.32 (m, 3H); 13C-NMR (CDCl3, 76 MHz) δ 146.5, 149.8, 140.0, 132.6, 131.4 (d, J=32.2 Hz), 128.0, 127.8, 127.7, 125.9, 123.8 (q, J=272.4 Hz), 122.8, 122.7, 122.0, 118.5, 111.6, 51.8, 50.2, 46.1, 40.1, 32.3, 31.9, 23.9. Mass spec.: 479.19 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[NH2:22][C:23]1[S:24][C:25]([CH3:28])=[CH:26][N:27]=1.Cl[C:30](OC)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:30](=[O:31])[NH:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Reactant: COC(=O)Cl
Reactant: Cc1cnc(N)s1
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(C)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that t-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that 2-amino-5-methylthiazole was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]([O-:21])=[O:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4].[OH-].[Li+].Cl>O1CCCC1.O>[OH:1][C@H:2]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4]
Reactant: C[C@H](NCCc1c[nH]c2c(OCC(=O)[O-])cccc12)[C@H](O)c1ccc(O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NCCc1c[nH]c2c(OCC(=O)O)cccc12)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 100 %

Procedure:
To a solution of ethyl (((3-(2-(((1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl)amino)ethyl)-1H-indol-7-yl)oxy)acetate (115 mg, 0.279 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) is added lithium hydroxide (10 mg, 0.418 mmol), and the mixture is stirred at room temperature for 11 hours. The pH value of the mixture is adjusted to pH 7 with 1N aqueous hydrochloric acid solution, and the solvent is distilled off. The obtained crude product is purified by octadecylsilyl (ODS) column chromatography (water→10% aqueous methanol) to give (((3-(2-(((1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1H-indol-7-yl)oxy)acetic acid (108 mg, 0.279 mmol, yield: 100%).