Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([NH2:17])=[C:11]3[C:18]#[N:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C1COCC1>[O:29]([C:27]([NH:17][C:12]1[NH:13][C:14]2[C:10]([C:11]=1[C:18]#[N:19])=[CH:9][C:8]([S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=2)=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1c(N)[nH]c2ccc(Sc3ccccc3)cc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c(NC(=O)Oc2ccccc2)[nH]c2ccc(Sc3ccccc3)cc12
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A solution of 5-phenylsulphanyl-2-amino-1H-indole-3-carbonitrile (0.43 g; 1.62 mmol) [Amphethinile, U.S. Pat. No. 4,533,672] in THF (5 ml) and pyridine (0.17 ml; 2.1 mmol) under argon was cooled to 0° C. and treated dropwise with phenyl chloroformate (0.25 ml; 2.0 mmol). The mixture was allowed to warm to room temperature overnight. After dilution with CH2Cl2 the organic phase was washed with water, then brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of Et2O/CH2Cl2 (5 to 10% Et2O) to give 2-phenoxycarbonylamino-5-phenylsulphanyl-1H-indole-3-carbonitrile as a beige solid (310 mg).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8](=[O:10])=[O:9]>>[C:8](=[O:10])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=O
Reactant: CCCCCCO
Product: CCCCCCOC(=O)OCCCCCC
Temperature: 30 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
Into the above-mentioned autoclave in which step (3) was performed was charged 61.5 g (602 mmol) of hexanol (manufactured and sold by Aldrich, U.S.A.; a dehydrated grade), and the autoclave was sealed. Then, from a carbon dioxide gas bomb, carbon dioxide gas, the pressure of which was lowered to 5 MPa by means of a pressure regulator connected to the carbon dioxide gas bomb, was introduced into the autoclave. Stirring of the contents of the autoclave was started. 10 Minutes after the start of the stirring, the valve of the carbon dioxide gas bomb was closed. Then, the internal temperature of the autoclave was elevated to 180° C. while stirring. In this instant, the internal pressure of the autoclave was about 7.5 MPa. Then, a reaction was performed for 6 hours while maintaining the internal pressure of the autoclave at about 7.5 MPa. Thereafter, the inside of the autoclave was cooled to about 30° C. and the internal pressure of the autoclave was returned to atmospheric pressure by gently purging the carbon dioxide gas through the purge line, and there was obtained a transparent reaction mixture. In the reaction mixture, dihexyl carbonate was obtained in a yield of about 14%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22]C3C=NC=CC=3)[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.CN1C(=O)CCC1.C([Mg]Cl)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.[Fe+3].C(OCC)(=O)C>[CH2:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: [Fe+3]
Agent: CC[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC2CNCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Boc-2-(3-hydroxy)benzylmorpholine, trifluoromethylsulfonate ester intermediate (a) (62 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL) and NMP (0.3 mL) under an atmosphere of nitrogen, at room temperature then iron (III) ac ethyl acetateetate (3 mg, 7.3 umol) was added in one portion to give an orange solution. To the reaction mixture was added ethylmagnesium chloride (2.0M solution in tetrahydrofuran, 0.11 mL, 0.22 mmol) dropwise over 2 minutes and the reaction stirred at room temperature for 30 minutes. Then more iron (III) ac ethyl acetateetate (6 mg, 14.6 umol) was added in one portion followed by ethylmagnesium chloride (2.0M solution in tetrahydrofuran, 0.24 mL, 0.48 mmol) dropwise over 3 minutes. After 30 minutes citric acid (10% w/w aqueous solution, 10 mL) and ethyl acetate (10 mL) was added and the mixture stirred vigorously for 5 minutes and left to stand for 18 hrs. The layers were separated and the aqueous layer extracted with ethyl acetate (10 mL). Combined organic layers were washed with water (10 mL), then brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (2.5 mL) and treated with TFA (1 mL) and stirred at room temperature for 3 hrs. The reaction was then poured through an SCX-2 column and washed with dichloromethane. The column was then washed with ammonia (2N, methanol) and the ammonia washes concentrated in vacuo. The residue was purified by preparative HPLC to yield the desired morpholine example 69 as an off-white solid (6 mg).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[CH3:3].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[C:8](=[O:18])[N:7]2[C:19]([CH3:22])=[CH:20][S:21][C:6]2=[N:5][C:4]=1[CH:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2)[CH3:3]
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)ccc3F)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)ccc3F)c(=O)n12
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.045 g, 0.14 mmol), 6-bromo-9H-purine (0.042 g, 0.21 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.3 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a mixture of two diastereomers (TFA salts). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1. Found: 440.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (1H, br s), 8.38 (1H, s), 8.36 (1H, s), 7.34˜7.19 (3H, m), 7.08 (1H, m), 5.06 (1H, m), 2.60 (3H, s), 1.46 (1.5H, d, J=6.8 Hz), 1.33 (1.5H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −117.8, −119.4, −119.8, −119.9 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[CH:36][CH:35]=1)[C:9]1[N:20]2[C:16](=[CH:17][CH:18]=[N:19]2)[N:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][N:13]2[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:43]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Cl:43][C:17]1[CH:18]=[N:19][N:20]2[C:16]=1[N:15]=[C:14]1[C:10]([CH2:11][CH2:12][N:13]1[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[C:9]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH3:42])=[CH:38][CH:39]=1
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4c(Cl)cnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF solution (2.0 mL) of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (12.5 mg, 0.0216 mmol), N-chlorosuccinimide (15.3 mg, 0.114 mmol) was added at room temperature and the mixture was stirred at room temperature for 1 hr. After the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=O)[C@H:15]([CH3:22])[CH2:16]1)[CH2:11][CH2:10]3.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[N:25][OH:26])[C@H:15]([CH3:22])[CH2:16]1)[CH2:11][CH2:10]3
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](C)C[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=NO)[C@H](C)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 17β-methoxy-2α-methyl-5α-androstan-3-one (Acta. Endocrinology 36, 83 (1961), 0.5 g.), hydroxylamine hydrochloride (0.218 g.) and sodium acetate (0.258 g.) in ethanol (20 ml.) is refluxed for 1 hour. Water is then added; a precipitate forms which is filtered, washed, dried and recrystallized from methylene chloride-acetone to give the title compound, m.p. 203°-211°; IR (mull) 3360 and 1650 cm-1 ; MS (me) 333; NMR (CDCl3) 0.75, 0.93, 1.06, 3.15 and 3.33 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:19])=[CH:11][C:12]=2/[CH:14]=[CH:15]/[C:16](O)=[O:17])[C:7]([CH3:20])=[CH:6]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.C(N(C(C)C)CC)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([S:64]([NH2:67])(=[O:66])=[O:65])[S:61][C:62]=1[Cl:63].Cl>ClCCl.O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:19])=[CH:11][C:12]=2/[CH:14]=[CH:15]/[C:16]([NH:67][S:64]([C:60]2[S:61][C:62]([Cl:63])=[C:58]([Cl:57])[CH:59]=2)(=[O:65])=[O:66])=[O:17])[C:7]([CH3:20])=[CH:6]1
Reactant: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)O)cc(F)cc12
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of (E)-3-[1-(2,4-dichloro-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-acrylic acid (10.0 g, 26.4 mmol) in dichloromethane (100 mL) was added EDCI (7.9 g, 41.2 mmol), HOBt hydrate (0.71 g, 5.3 mmol), and diisopropylethylamine (10.6 g, 81.8 mmol), and the mixture was stirred for 20 mm. To the reaction was added 4,5-dichlorothiophene-2-sulfonamide (6.43 g, 27.2 mmol), and the mixture was stirred at room temperature for 15 mm, then at reflux for 16 h. The reaction was cooled to room temperature then diluted with 25 mL water followed by 25 mL 2 M HCl. The mixture was stirred for 5 mm, then the phases were split. The organic phase was diluted with 25 mL of 2 M HCl and stirred, which induced precipitation of the product. The temperature was reduced to 0° C., and stirring was continued for 1 h. The product was collected via vacuum filtration, washed with water (3×25 mL) and heptanes (2×25 mL), then vacuum dried at 60° C. to afford 9.3 g (60% yield) of the title compound. The product could be further purified via recrystallization from ethanol: 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 5.53 (s, 2H), 6.12 (d, 1H, J=8.4 Hz), 6.21 (d, 1H, J=15.4 Hz), 7.04 (dd, 1H, J=10.0, 2.4 Hz), 7.22 (dd, 1H, J=8.4, 2.0 Hz), 7.37 (s, 1H), 7.38 (d, 1H, J=2.0 Hz), 7.46 (dd, 1H, J=9.2, 2.4 Hz), 7.74 (d, 1H, J=15.4 Hz), 7.90 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9][CH3:10])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9]([CH3:10])=[O:16])[CH:7]=1
Reactant: CSCc1cncc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
3-Bromo-5-methylsulfanylmethyl-pyridine (6.0 g, 28 mmol) is dissolved in chloroform (200 mL) and the solution is cooled to 0° C. Meta-chloroperoxybenzoic acid (7.2 g, 30 mmol, 72%) is added slowly at 0° C. and the reaction mixture is stirred at 0° C. for 1 hr. Then the solvent is removed and the residue is purified by flash column chromatography to give 3.5 g of 3-bromo-5-methanesulfinylmethyl-pyridine.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](/[C:20]2[NH:25][C:24](=[O:26])[C:23]([CH3:27])=[CH:22][CH:21]=2)\[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:20]2[NH:25][C:24](=[O:26])[C:23]([CH3:27])=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:18][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(CC2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1=O

Procedure:
10% palladium-activated carbon (50 mg) was added to a mixed solution of 6-{(E)-2-cyclopentyl-1-[4-(cyclopropylsulfonyl)phenyl]ethenyl}-3-methylpyridin-2(1H)-one synthesized in Example 1-11 (50 mg) in tetrahydrofuran and methanol (2 mL, 1:1), and the mixture was stirred in a hydrogen gas stream at room temperature for three hours. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:1→0:1) to give the title compound as a colorless amorphous (33 mg, 60%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:14]=[O:15]>[OH-].[Na+]>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[C:8]([CH2:14][OH:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=O
Reactant: CCc1ccc2c(O)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(O)c(CO)cnc2c1

Procedure:
7-Ethyl-4-hydroxyquinoline was reacted with 40% aqueous formaldehyde in aqueous sodium hydroxide to give the novel compound 7-ethyl-4-hydroxy-3-hydroxymethylquinoline, m.p. 180°-182°.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:20])[CH:10]=1)=O)(C)(C)C>OS(O)(=O)=O.CCOC(C)=O>[NH2:8][C:9]1[CH:10]=[C:11]([Cl:20])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:17]([Cl:19])[CH:18]=1
Reactant: COC(=O)c1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)cc(N)cc1Cl
Yield: 55.6 %

Procedure:
A solution of methyl 4-(tert-butoxy carbonylamino)-2,6-dichlorobenzoate (65 g, 0.49 mol) in H2SO4/EtOAc (3 N, 20 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the solid was collected to afford methyl 4-amino-2,6-dichlorobenzoate (60 g, yield: 92%). 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (brs, 3H), 6.61 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Fc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCCSc1ccc(F)cc1
Temperature: 80 °C

Procedure:
4-Fluorobenzenethiol (0.50 ml, 4.69 mmol) and 2-bromoethanol (0.345 ml, 4.87 mmol) was dissolved in tetrahydrofuran (12 ml). The solution was added with 1N aqueous solution of sodium hydroxide (4.8 ml,4.8 mmol) and heated at 80° C. for 80 minutes with stirring. The reaction mixture was diluted with a mixed solvent of ethyl acetate-hexane, and washed with diluted aqueous solution of sodium hydroxide, water, and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration and the filtrate was concentrated under reduced pressure to obtain 2-(4-fluorophenylthio)ethanol as crude product. By using the resulting product, 2-(4-fluorophenylthio)ethanol ethanesulfonate was obtained as crude product by similar procedures to those of Example 26a. By using the resulting product, the title compound was obtained as colorless solid by similar procedures to those of Example 26b (yield: 64%).
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.C(O)(=O)C.[CH3:14][O:15][C:16]1[C:17]([CH3:31])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21]1([CH2:29][CH2:28][CH2:27]1)[CH2:20][CH:19]2O>C1COCC1>[CH3:14][O:15][C:16]1[C:17]([CH3:31])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21]1([CH2:27][CH2:28][CH2:29]1)[CH2:20][CH2:19]2
Reactant: COc1c(C)cc2c(c1C)C(O)CC1(CCC1)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cc2c(c1C)CCC1(CCC1)N2
Reaction time: 0.5 h

Procedure:
To a mixture of NaBH4 (1 g) added in portions to a solution of cooled trifluoroacetic acid and acetic acid (30 mL, v/v: 1/1), was added 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinolin]-4′-ol in 10 mL THF. After 30 minutes, the reaction mixture was quenched with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried with Na2SO4, evaporated, and purified by column chromatography (1-2% methanol in CH2Cl2), to give 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinoline] as a brown oil (500 mg).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([CH:63]1[C:70]2[CH:69]=[C:68]([C:71]([O:73]C)=[O:72])[NH:67][C:66]=2[CH2:65][CH2:64]1)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(#N)C.O>[Br:1][C:69]1[C:70]2[CH:63]([CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:64][CH2:65][C:66]=2[NH:67][C:68]=1[C:71]([OH:73])=[O:72]
Reactant: [Br-]
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: O=C(O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
Tetrabutylammonium tribromide (114 mg, 0.24 mmol) was added to a solution of methyl 4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (53 mg, 0.2 mmol) in 5 mL of acetonitrile at room temperature. After reacting overnight, the reaction was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated with silica gel. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane gave the title compound. 54.2 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69-1.80 (m, 1H), 2.10-2.22 (m, 2H), 2.56-2.71 (m, 4H), 2.72-2.83 (m, 1H), 3.00-3.09 (m, 1H), 3.80 (s, 3H), 7.11-7.16 (m, 1H), 7.17-7.21 (m, 2H), 7.22-7.27 (m, 2H); LCMS-MS (ESI+) 372.0 (M+Na).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([I:12])[CH:11]=1)[NH:8][C:7](=[S:13])[N:6]([CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[C:5]2=[O:20].[CH2:21](I)[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([I:12])[CH:11]=1)[N:8]=[C:7]([S:13][CH2:21][CH2:22][CH3:23])[N:6]([CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[C:5]2=[O:20]
Reactant: CCCI
Reactant: O=c1c2cc(I)cc(I)c2[nH]c(=S)n1CC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(I)cc(I)cc2c(=O)n1CC1CCCO1
Yield: 88.3 %

Procedure:
A mixture of the title compound of Step A (0.86 g, 1.67 mmol), n-propyl iodide (0.85 g, 5.02 mmol) and potassium carbonate (2.3 g, 16.7 mmol) was stirred in dimethylformamide (20 mL) at ambient temperature for approximately 4 h. The reaction mixture was then concentrated to dryness in vacuo and partitioned between 200 mL each of ethyl acetate and water. The organic phase was then separated, washed with saturated aqueous NaCl, and dried over Na2SO4. Concentration in vacuo provided 0.82 g of the title compound of Step B, a compound of the invention, as a solid melting at 108-111° C. 1H NMR (300 MHz, CDCl3): δ 1.10 (t,3H), 1.63-1.80 (m,1H), 1.80-2.14 (m,5H), 3.24-3.45 (m,2H), 3.70-3.80 (m,1H), 3.90-4.00 (m,1H), 4.10-4.21 (m,2H), 4.35-4.47 (m,1H), 8.44 (d,1H), 8.48 (d,1H).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[C@@H:18]([CH3:23])[CH2:19][NH:20][C:21](=[O:22])[C:13]3=[CH:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[C@@H:18]([CH3:23])[CH2:19][NH:20][C:21](=[O:22])[C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: C[C@H]1CNC(=O)c2cc3cc(OCc4ccccc4)ccc3n21
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC(=O)c2cc3cc(O)ccc3n21
Yield: 100 %

Procedure:
The suspension consistent of 3.50 g (11.4 mmol) (S)-8-benzyloxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one and 0.35 g palladium on activated charcoal (10% Pd; commercially available) in 40 mL methanol was hydrogenated at room temperature at 1.5 bar for 3 hours. The reaction mixture was filtered over Dicalite Speed Plus® (Aldrich) and the volatile components were evaporated at a rotary evaporator to give the desired compound as a light yellow foam (100%) which was used in the next step without further purification.
Reaction SMILES: O=C1CCCCC1C(OCC)=O.Br[C:14]1[C:19]([F:20])=[CH:18][C:17]([C@@H:21]([NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH3:22])=[C:16]([F:30])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40]>CCOC(C)=O.[Cu]I>[F:30][C:16]1[CH:15]=[C:14]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[C:19]([F:20])=[CH:18][C:17]=1[C@@H:21]([NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH3:22]
Reactant: OCC(F)(F)F
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(Br)cc1F
Agent: [Cu]I
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(OCC(F)(F)F)cc1F
Temperature: 78 °C
Yield: 98.1 %

Procedure:
To a mixture of ethyl 2-oxocyclohexanecarboxylate (58.0 mg, 0.341 mmol), (R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (580 mg, 1.705 mmol), Cs2CO3 (1555 mg, 4.77 mmol), copper(I) iodide (32.5 mg, 0.170 mmol) was added 2,2,2-trifluoroethanol (871 μl, 11.93 mmol). The reaction was sealed and heated at 78° C. for 24 hours. LCMS indicated complete conversion to product. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL). The mixture was filtered through a pad of celite and the pad was rinsed with EtOAc (20 mL). The organic was washed with water (2×15 mL), dried (Na2SO4) and concentrated. The residue was then filtered through a pad of silica gel (30 g) with EtOAc/heptane (1:3) to give crude (R)—N—((S)-1-(2,5-difluoro-4-(2,2,2-trifluoroethoxyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.601 g). LCMS (B) m/z 360.1 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[S:4]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10](OC)=[C:9]([O:16]C)[CH:8]=1)(=[O:6])=[O:5])[CH3:2].B(Br)(Br)Br.[OH2:24].Cl>ClCCl>[CH2:1]([N:3]([CH2:18][CH3:19])[S:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([OH:16])[C:8]=1[OH:24])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1cc(Cl)c(OC)c(OC)c1
Reactant: O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cc(Cl)cc(O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 0.7 g of N,N-diethyl-5-chloro-3,4-dimethoxybenzenesulfonamide in 10 ml of dichloromethane 9.0 ml of 1 molar BBr3 in dichloromethane was added. The solution was stirred overnight at room temperature. Water and hydrochloric acid were added and the mixture was extracted with dichloromethane. The solvent was evaporated. Yield 0.3 g (47%), m.p. 62°-64° C.