Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]#[N:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.[Sn]([N:39]=[N+:40]=[N-:41])(C)(C)C>C1(C)C=CC=CC=1>[NH:39]1[C:32]([CH2:31][CH2:30][C@@:20]2([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18](=[O:34])[N:17]([C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:10][CH:11]=3)[CH3:16])[CH2:22][CH2:21]2)=[N:33][N:41]=[N:40]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC#N)(c2ccc(F)cc2)OC1=O
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCc2nnn[nH]2)(c2ccc(F)cc2)OC1=O
Yield: 22.9 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanenitrile (40 mg, 0.086 mmol) in anhydrous toluene (3 mL) was added Me3SnN3 (89 mg, 0.43 mmol) at 0° C. The mixture was refluxed overnight. The solvent was removed under reduced pressure and the residue was purified by preparative TLC to afford (R)-6-(2-(1H-tetrazol-5-yl)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (10 mg, yield: 22%). 1H NMR (CDCl3): 1.20 (m, 3H), 1.73-1.88 (m, 1H), 1.91-2.07 (m, 4H), 2.20-2.31 (m, 1H), 2.58-2.77 (m, 2H), 5.43 (m, 1H), 6.67-6.90 (m, 7H), 7.01 (m, 2H), 7.11 (m, 2H), 7.18 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[CH3:15][N:16]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[C:15]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1)#[N:16]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)n1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-6-(trifluoromethyl)pyridine-2-carboxylic acid (0.150 g, 0.556 mmol, Anichem) and zinc cyanide (0.39 g, 3.3 mmol) were mixed in N-methylpyrrolidinone (2 mL) and the mixture was degassed by bubbling a stream of nitrogen through the mixture for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.096 g, 0.083 mmol) was added, the degassing was continued for 5 minutes, then the reaction was sealed and heated in the microwave to a temperature of 160° C. for 15 minutes. The mixture was filtered and purified by preparative HPLC (eluting with a gradient from 18.8 to 40.9% MeCN/H2O containing 0.1% TFA over 1-6 min at 60 mL/min thru C18 SunFire 30×100 mm, 5 um particle size) using UV detection. The product eluted at 5.25 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[NH4+]>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:2][CH2:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC1CCNCC1
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCC(O)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
4-piperidinol (2 g, 19.8 mmol) was added to dichloromethane (20 mL), and cooled to an internal temperature of 0-5° C. Then, triethylamine (3.31 mL, 23.7 mmol) was added thereto and stirred for 30 min. Pivaloyl chloride (2.62 g, 21.8 mmol) was dropwise added thereto and heated to room temperature. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with a saturated aqueous solution of ammonium (50 mL) and extracted twice with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (3.9 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=[O:3])[CH3:2].C(O)C.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH2:24][CH2:23]1>N1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:26]1[C:22](=[O:28])[CH2:23][CH2:24][C:25]1=[O:27])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CO1
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCC(O)CN1C(=O)CCC1=O

Procedure:
0.072 mol (18.2 g) of 1-(2'-acetylamino-5'-nitrophenoxy)-2,3-epoxypropane is introduced into 60 ml of absolute ethanol to which 6 drops of pyridine have been added. 0.087 mol (8.6 g) of succinimide is added and the mixture is then heated under reflux for 5 hours. After cooling, 150 ml of water are added and the alcohol is driven off in vacuo. The expected product, which is obtained initially in the form of a water-insoluble oil, crystallises slowly. It is filtered off and recrystallised from 96° strength alcohol. After drying, it melts at 157° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:16](=O)[CH2:15]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:15][CH2:16][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:18]2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)CC1=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.8 %

Procedure:
Under a nitrogen atmosphere, 1 mol/l borane-tetrahydrofuran complex solution (5.6 ml) was added dropwise to a tetrahydrofuran solution (15 ml) of 4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (isomer B1) (700 mg, 1.88 mmol) under ice cooling, followed by stirring at room temperature for 13 hours. After removal of the solvent under reduced pressure, 80% water-containing ethanol (15 ml) and triethylamine (3 ml) were added to the residue and the mixture was heated under reflux for 4 hours. After cooling on standing, the solvent was removed under reduced pressure and chloroform (30 ml) was added to the resulting residue. The solution was washed with water (10 ml) and saturated saline (10 ml) and then, dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography to obtain the title compound (565 mg, 84%) as colorless crystals from the fraction eluted with chloroform/methanol=20/1.
Reaction SMILES: [CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2>C1COCC1.[Pd]>[CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([NH2:12])[CH:10]=2
Reactant: C[C@@]1(c2ccccc2)CCN2CC[C@@](C)(c3ccccc3)c3cc([N+](=O)[O-])cc1c32
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@@]1(c2ccccc2)CCN2CC[C@@](C)(c3ccccc3)c3cc(N)cc1c32

Procedure:
A mixture of (1S,7S)-1,7-dimethyl-9-nitro-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline (7), (2 g, 5 mmol), in THF (60 mL) was subjected to hydrogenation reaction by the action of 10% Pd/C (200 mg) under H2 balloon at room temperature for 12 h. The mixture was filtered through Celite and freed of solvent under reduced pressure to get (1S,7S)-1,7-dimethyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (9) as a solid, (1.5 g, 100%) on the basis of recovered starting material (7), (390 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH3:12])[CH:5]=[CH:4][C:3]=1[NH:20][C:21](=[O:41])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.Cl>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][NH:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:20][C:21](=[O:41])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)=[CH:24][CH:23]=1
Reactant: Cc1cc(OCCN(C)C(=O)OC(C)(C)C)ccc1NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCOc1ccc(NC(=O)c2ccc(N3CCNCC3)cc2)c(C)c1
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and a gas dispersion tube was added N-(2-methyl-4-(2-(1,1-dimethylethoxycarbonyl(methyl)amino)ethoxy)phenyl)-4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)benzamide (0.620 g, 1.09 mmol) and 40 mL of dry EtOAc. This well stirred solution was cooled to 0° C. in an ice bath and was saturated with HCl gas for over 15 min. The reaction was aged for an hour and excess HCl was removed with a stream of argon. Removal of EtOAc in vacuo and the crude HCl salt was converting to freebase by dissolving in saturated NaHCO3 solution. Extracted with EtOAc and the layers were separated. A white solid precipitated out from the aqueous and was collected via suction filtration. This crude product was recrystallized from hot MeOH-Et2O to give 0.175 g of N-(2-methyl-4-(2-methylaminoethoxy)phenyl)-4-(1-piperazinyl)benzamide as a white solid. mp: 136-137° C. 1H NMR (DMSO-d6): d 2.28 (s, 3H), 2.50 (s, 3H), 2.95 (m, 2H), 3.03 (m, 4H), 3.27 (m, 4H), 4.06 (m, 2H), 6.78 (d, j=6 Hz, 2H), 6.93 (d, j=9 Hz, 2H), 7.41 (s, 1H), 7.65 (d, j=9 Hz, 1H), 7.79 (d, j=9 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)C.O[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:26][C:25]2=[O:38].CC(OC(/N=N/C(OC(C)C)=O)=O)C.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][C:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][C:25]3=[O:38])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: CCOC(=O)C(Cc1ccc(C#CCCO)cc1)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Cc1ccccc1
Product: CO[C@@H](Cc1ccc(C#CCCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(4-Hydroxy-but-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 47, Step A and 6-hydroxyflavone following the standard coupling-hydrolysis procedure A using toluene as solvent and DIAD instead DEAD. MS(ES) for C29H24O6 [M+H]+: 469.2.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)[CH:31]=O)[CH3:26]>ClC(Cl)C.ClCCl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1cc(C=O)cc(OCC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(C=C(Br)Br)cc(OCC)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Carbon tetrabromide (4.78 g) was dissolved in dichloroethane (14 mL), and triphenylphosphine (7.56 g) was added thereto at 0° C. After stirring at 0° C. for 5 minutes, a solution of 3,5-diethoxybenzaldehyde (1.40 g) in dichloromethane (7 mL) was added thereto, followed by stirring for 20 minutes. Without performing further treatment, the reaction mixture was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate) to obtain 1-(2,2-dibromovinyl)-3,5-diethoxybenzene. The obtained compound was used for the subsequent reaction without further purification. The compound obtained above was dissolved in THF (30 mL). A 1.63 M n-butyllithium solution in hexane (10.5 mL) was added thereto at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes. After adding a saturated aqueous ammonium chloride solution, the reaction mixture was subjected to extraction using ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, and the organic layer was then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (1.31 g). Physical properties: m/z [M+H]+ 191.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=[CH2:31])[C@H:10]([N:26]=[N+:27]=[N-:28])[C:11](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.[Li+].[BH4-]>CO>[N:26]([C@@H:10]([C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:29][CH:30]=[CH2:31])[CH2:11][OH:12])=[N+:27]=[N-:28]
Reactant: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@@H](CO)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 3-(3(S)-(3,4-dichlorophenyl)-2(S)-azido-1-oxo-5-hexenyl)-4(S)-benzyl-2-oxazolidinone (890 mg, 1.94 mmol) and THF (25 mL) at 0° C. was added MeOH (126 mL, 3.1 mmoL), followed by LiBH4 (68 mg, 3.1 mmol). The mixture was allowed to stir for 2 h, and was then quenched by addition of sat. aq. Rochelle salts (50 mL) and was allowed to warm to room temp and stirred vigorously for 2 h. The mixture was diluted with H2O (150 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, 10-40% EtOAc/hexanes) to afford the alcohol (452 mg, 82%) as a colorless oil.
Reaction SMILES: [CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[O:3][CH2:2]1.[Br-:11].[Li+].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]1[O:10][C:4]([CH2:6][CH2:7][CH2:8][Br:11])([CH3:5])[O:3][CH2:2]1
Reactant: [Br-]
Reactant: CC1(CCCCl)OCCO1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(CCCBr)OCCO1

Procedure:
4.0 Parts of 5-chloro-2-pentanone ethylene ketal is mixed with 9.0 parts of lithium bromide and 2.0 parts of diisopropylethylamine in 30 parts by volume of tetrahydrofuran which has been distilled from lithium aluminum hydride. The mixture is refluxed under nitrogen for 48 hours, cooled and poured into a mixture of ether and water for extraction. The ether layer is washed twice with water, then with 1 N hydrochloric acid and then twice again with water. The ether layer is then dried over sodium sulfate and evaporated under reduced pressure to give 5-bromo-2-pentanone ethylene ketal of formula XXI of Chart C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([NH2:20])=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]#[N:20])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(N)=O)cc1CCS(=O)(=O)CCC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCn1nc(C#N)cc1CCS(=O)(=O)CCC
Temperature: 25 °C
Yield: 101 %

Procedure:
1-Butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide (4.00 g, 13.27 mmol) in toluene (66 mL) was treated with phosphorous oxychloride (2.50 mL, 26.5 mol). The solution was heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The resulting oil was diluted with water (50 mL) and saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 3.8 g of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[N:10]=[CH:9][C:8]=1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:50]>>[ClH:50].[ClH:50].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[N:10]=[CH:9][C:8]=1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCNc1cc(C(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1cc(C(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl (3S,5R)-3-[({4-[(3-methoxypropyl)amino]-6-(1-methylethyl)pyridin-3-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (268 mg) was dissolved in 4 M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. Aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 4 M Hydrogen chloride-ethyl acetate (1 ml) was added to the residue, and the mixture was stirred for 5 min and concentrated under reduced pressure to give the object compound (163 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18]C(=O)C.S(=O)(=O)(O)O>CO.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[C:7]([C:14]([F:16])([F:15])[F:17])=[CH:6][C:5]=1[NH2:18]
Reactant: CCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 60 °C
Yield: 81.7 %

Procedure:
A solution of 2-acetylamino-5-propionyl-4-trifluoromethyl-benzoic acid methyl ester (260 mg, 0.82 mmol) in MeOH (2.6 mL) and water (0.54 mL) was treated with concentrated sulfuric acid (0.26 mL) and the mixture was heated to 60° C. for 1 h. It was then allowed to cool to r.t., and diluted with EtOAc. This mixture was washed once with aqueous sodium hydrogencarbonate (pH=8), once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 100:0→80:20) to furnish 2-amino-5-propionyl-4-trifluoromethyl-benzoic acid methyl ester (185 mg, 0.67 mmol, 82%) as a white powder, m.p. 141-144° C., ESI-MS: m/z 276 [M+H]+.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][CH:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH:23]=4)[C:21]#[N:22])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CCC4O)s2)cc1C#N
Reactant: NCCO
Product: CC(C)Oc1ccc(-c2ccc(-c3cccc4c3CCC4NCCO)s2)cc1C#N

Procedure:
Prepared using General Procedure 20 from 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile and ethanolamine. LCMS-ESI (m/z) calculated for C25H26N2O2S: 418.2; found 419.1 [M+H]+, tR=2.73 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH2:33][C:34](OC)=[O:35])=[CH:27][C:26]=2[CH3:38])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[NH3:39]>O1CCOCC1>[NH2:39][C:34](=[O:35])[CH2:33][O:32][C:28]1[CH:29]=[C:30]([CH3:31])[C:25]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:26]([CH3:38])[CH:27]=1
Reactant: COC(=O)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Reactant: N
Solvent: C1COCCO1
Product: Cc1cc(OCC(N)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from 2-((S)-6-((R)-7-fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid and 0.5 M solution of ammonia in 1,4-dioxane following a procedure analogous to that described in example 12. LC (method 9): tR=1.01 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([I:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([I:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCCCCCOc1c(I)cc(I)cc1I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCOc1c(I)cc(I)cc1I
Yield: 89 %

Procedure:
Ethanol (95%, 30 mL) was added with of ethyl 7-(2,4,6-triiodophenoxy)heptanoate (4.0 g) and the mixture was refluxed for dissolution, and the solution was added with sodium hydroxide (0.5 g) and further refluxed for 1.5 hours. The crystals obtained were separated by filtration, washed with ethanol and added with dichloromethane and 1 N hydrochloric acid to conduct extraction twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed. The resulting residue was purified by silica gel column chromatography to obtain 7-(2,4,6-triiodophenoxy)heptanoic acid (3.4 g, yield: 90%).
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N>CO.[Ni]>[S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][NH2:21])[CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(C#N)cc32)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CN)cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
To a solution of 34 (100 mg, 0.34 mmol) and 7 M ammonia solution in MeOH (5 mL) was added Raney Ni (10 mg) and the mixture was stirred vigorously under H2 (1 atm.) atmosphere at RT for 18 h. The catalyst was filtered was and the filtrate concentrated in vacuo to afford 80 mg (78%) of (1-tosyl-1H-indol-6-yl)methanamine (36) as syrup: MS (ESI) m/z=301.2 [M+1]+.