Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:41]=[CH:40][C:9]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH:31]C(OCC(Cl)(Cl)Cl)=O)[CH:27]=5)[CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)(=O)C.[Zn]>[NH2:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:41][CH:40]=3)[CH2:17][CH2:16]1)(=[O:20])=[O:19])[CH:30]=[CH:29]2
Reactant: O=C(Nc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4ccc(-n5ccnc5)cc4)CC3)ccc2c1)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4ccc(-n5ccnc5)cc4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
To a solution of 1-[4-(1-imidazolyl)benzoyl]-4-[6-(2,2,2-trichloroethoxycarbonylamino)naphthalene-2-sulfonyl]piperazine (400 mg) in acetic acid (5 ml) was added zinc powder (1 g), and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered, and the filtrate was concentrated. The residue was dissolved in 0.5 N hydrochloric acid, washed with ethyl acetate and made alkaline with 1 N sodium hydroxide aqueous solution. The precipitate was collected by filtration, washed with water and dried to give a colorless solid of the title compound (187 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:4]1=[O:17].[Cl:18]C1C=CC(B(O)O)=CC=1>>[ClH:16].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)[C:4]1=[O:17]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Agent: Cl
Product: N[C@H]1CCCCN(c2ccc(Cl)cc2)C1=O

Procedure:
(S)-3-Amino-1-(4-chlorophenyl)azepan-2-one hydrochloride (35 mg, 0.127 mmol) was synthesized as described for the preparation of Intermediate 49 using 4-chlorophenylboronic acid in step A. Anal. Calcd. for C12H15ClN2O m/z 238.8. found: 239.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[C:16]([S:20]([NH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=O)[CH2:26][CH2:25]1)(=[O:22])=[O:21])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([S:20]([NH:23][C@@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]2[NH:8][C:7]3[C:2](=[N:3][C:4]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)=[N:5][CH:6]=3)[N:1]=2)[CH2:28][CH2:29]1)(=[O:22])=[O:21])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: Nc1cnc(-c2ccc(F)cc2)nc1N
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](c2nc3nc(-c4ccc(F)cc4)ncc3[nH]2)CC1

Procedure:
By following the same procedure as described in Example 1 except that use was made of 4,5-diamino-2-(4-fluorophenyl)pyrimidine and cis-4-tert-butylsulfonylaminocyclohexanecarboxylic acid in place of 4-trifluoromethyl-1,2-phenylenediamine, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.N1C=CC=CC=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:15][N:14]1[C:5]2[C:4]3[N:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[C:12]([C:16]([NH2:18])=[O:17])=[N:13]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cn1nc(C(N)=O)c2ccc3cnc(N)nc3c21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1nc(C(N)=O)c2ccc3cnc(NC(=O)Cc4ccccc4)nc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
0.40 g (1.47 mmol) of 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were suspended in 20 mL of tetrahydrofuran and 5 mL of pyridine and 0.42 mL (3.22 mmol) of phenylacetylchloride were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, the residue redissolved with dichloromethane, washed with aqueous NaHCO3 and then with water. After drying over anhydrous Na2SO4 the solvent was removed under reduced pressure and the crude purified by chromatography on a silica gel column (eluant cyclohexane/acetone) giving 0.35 mg of the title compound (60% yield).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>C1COCC1>[C:16]([Si:20]([O:26][C:24]([O:27][CH2:28][CH3:29])=[CH2:25])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(C)=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(OCC)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (17.34 mL, 102.14 mmol) in THF (63.4 mL) under argon, 2.9 M BuLi in hexanes (34.05 mL, 98.74 mmol) was added dropwise at 0° C. The reaction was stirred for 15 min. and subsequently cooled to −78° C. t-Butyldimethylchlorosilane (TBDMSCl) (16.94 g, 112.36 mmol) in THF (25.4 mL) was added and then a solution of anhydrous ethyl acetate (8.38 mL, 85.12 mmol) in THF (57.2 mL) was slowly added over 1 h. The mixture was stirred for an additional 10 min at −78° C. and then stirred at r.t. for 1 h. The solution was then diluted with hexanes (285.9 mL), filtered through a Celite pad, and the filtrate concentrated. Distillation under vacuum at 42-50° C. gave an orange oil (g, 2.0%). 1H NMR (400 MHz, CDCl3) δ 3.74 (q, 2H, J=7.0 Hz, CH2), 3.22 (d, 1H, J=2.0 Hz, CH2), 3.05 (d, 1H, J=2.0 Hz, CH2), 1.29 (t, 3H, J=7.1 Hz, CH3), 0.94 (s, 9H, CH3), 0.17 (s, 6H, CH3); 13C NMR (400 MHz, CDCl3) δ 160.3, 62.4, 59.6, 24.79, 17.3, 13.5, −5.4
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Na].[C:10](=[O:12])=[O:11]>C1CCCCC1>[C:5]1([CH2:8][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C=O
Reactant: Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: C1CCCCC1
Product: O=C(O)Cc1ccccc1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
In accordance with the process of Example 1, 12.7 g of p-chlorotoluene were contacted and reacted with 5.4 g of sodium dispersed in 50 ml of cyclohexane at 20° C to 30° C and then the reaction mixture was heated to 80° C for 5 hours to rearrange the product. The reaction mixture was cooled to 20° C to 23° C and was gradually poured onto 10 g of solid carbon dioxide with stirring to effect the carbonylation reaction. After the reaction with carbon dioxide, the post-treatment procedure was conducted in accordance with the process of Example 1 to whereby 12.8 g of phenylacetic acid (yield 94.1%) were obtained.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12].C(N(CC)CC)C>C(O)C>[C:4]1([CH2:3][CH2:2][C:1](=[O:10])[CH2:12][CH2:11][C:13](=[O:14])[CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)CCc1ccccc1

Procedure:
67.1 g (0.5 mol) of hydrocinnamaldehyde, 35.1 g (0.5 mol) of methyl vinyl ketone, 13.5 g (0.05 mol) of Cat. 1, 20.2 g (0.2 mol) of triethylamine and 500 ml of ethanol are brought together, in the manner described in Example 1. The product is worked up as described in Example 21. Fractional distillation gives 1-phenyl-heptane-3,6-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]3[CH2:21][CH2:20][C@@:19]4([CH2:25][CH2:24][N:23]([CH3:26])[C:22]4=[O:27])[NH:18]3)[CH:12]=1)[NH:7][N:6]=[CH:5]2.N(C(OC(C)(C)C)=O)=NC(O[C:33](C)(C)[CH3:34])=O.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:33]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]4[CH2:21][CH2:20][C@@:19]5([CH2:25][CH2:24][N:23]([CH3:26])[C:22]5=[O:27])[NH:18]4)[CH:12]=3)[CH:9]=2)[CH:5]=[N:6]1)[CH3:34]
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc5[nH]ncc5cc4F)ccn3)N2)C1=O
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1ncc2cc(F)c(-c3ccnc([C@H]4CC[C@@]5(CCN(C)C5=O)N4)c3)cc21
Temperature: 800 °C

Procedure:
To a Smith microwave vial was added (2R,5S)-2-[4-(5-fluoro-1H-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Example 186) (40 mg, 0.1100 mmol), di-tert-butyl azodicarboxylate (126.03 mg, 0.5500 mmol), ethanol (0.03 mL, 0.5500 mmol) and triphenyl phosphine (143.56 mg, 0.5500 mmol) in THF (1 mL). The reaction mixture was heated by microwave at 800° C. for 45 minutes. The reaction mixture was cooled and eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed by MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave a colourless oil. The crude residue was purified by silica gel chromatography (silica 10 g) eluting with methanol (containing 10% 0.88 ammonia) in ethyl acetate (0-80%), to give the products as a mixture of isomers. These were separated by HPLC using a ChiralPak IA column and eluting with ethanol/n-heptane (20%:80%) to give (2R,5S)-2-[4-(1-ethyl-5-fluoro-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one as the major isomer;
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=2)[C:22]([OH:24])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][C:59]1([CH3:66])[O:63][CH:62]([CH2:64][NH2:65])[CH2:61][O:60]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:58][C:59]1([CH3:66])[O:63][CH:62]([CH2:64][NH:65][C:22](=[O:24])[C:21]2[CH:25]=[C:17]([C:12]3[C:13]4[C:8](=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:10][N:11]=3)[CH:18]=[N:19][CH:20]=2)[CH2:61][O:60]1
Reactant: CC1(C)OCC(CN)O1
Reactant: O=C(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OCC(CNC(=O)c2cncc(-c3nnc(NCc4ccccn4)c4c(-c5ccccc5)cccc34)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinic acid (0.200 g, 0.461 mmol) in DMF (5 mL) was added HATU (0.526 g, 1.38 mmol) at ambient temperature. DMAP (0.169 g, 1.38 mmol) was added followed by (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.0610 g, 0.461 mmol, commercial) and the contents were stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 12 g, 50% EtOAc/hexanes) to obtain N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) phthalazin-1-yl)nicotinamide (0.0300 g, 11.9%) as an off-white solid. LCMS (Condition 7): retention time 1.76 min, [M+1]=547.2. HPLC (Condition 24): retention time 7.68 min, Purity 96.10%. 1H NMR (400 MHz, DMSO-d6) δ 1.27 (s, 3H), 1.36 (s, 3 H), 3.31-3.51 (m, 2 H), 3.74 (dd, J=5.6 Hz, J=8.4 Hz, 1 H), 4.03 (dd, J=6.0 Hz, J=8.4 Hz, 1 H), 4.26 (m, 1 H), 4.66 (d, J=4.0 Hz, 2 H), 6.33 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.22 (dd, J=5.2 Hz, J=6.4 Hz, 1 H), 7.29 (d, J=6.8 Hz, 1 H), 7.50-7.59 (m, 5 H), 7.69-7.73 (m, 2 H), 7.84 (dd, J=1.6 Hz, J=8.0 Hz, 1 H), 7.93 (dd, J=7.2 Hz, J=8.0 Hz, 1 H), 8.23 (d, J=4.8 Hz, 1 H), 8.51 (t, J=2.0 Hz, 1 H), 8.94 (dd, J=5.6 Hz, J=6.0 Hz, 1 H), 9.0 (d, J=2.0 Hz, 1H), 9.16 (d, J=2.0 Hz, 1 H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:7][CH2:6][CH2:5]2.OS(O)(=O)=O.N([O-])=O.[Na+].[BrH:23]>CO.O.CCOC(C)=O>[Br:23][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2c(cc1Br)CCC2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-Amino-6-nitroindane (4 g) is dissolved in 10 mL of MeOH, 30 mL of H2O and 20 mL of H2SO4, and cooled to 0° C. A solution of 1.72 g of NaNO2 (24.9 mmol) in 5 mL of H2O is added dropwise, keeping the temperature of the reaction below 8° C. The mixture is allowed to stir for 30 minutes. This mixture is then added dropwise to a mixture of CuBr (1.8 g, 12.5 mmol) and 6 mL of 48% HBr in 30 mL of H2O that is heated to 60° C. The reaction is cooled and added to H2O and EtOAc. The organic layer is separated and the solvents evaporated in vacuo to give a residue that is purified by silica gel chromatography (75% hexane/EtOAc) to give 5-bromo-6-nitroindane. A mixture of this indane (2.59 g, 12.2 mmol), 4.88 g (27.2 mmol) of tetramethyltin, 0.1 g of Pd(OAc)2 (0.45 mmol), 0.3 g (O-tol) 3P (0.98 mmol), 7 mL of Et3N and 7 mL of DMF is heated in a sealed tube to 65° C. for 3 days. The mixture is acidified with 1 N HCl and extracted with EtOAc. The organic layer is washed with saturated brine and dried over Na2SO4 and the solvents are evaporated in vacuo to give a residue that is purified by column chromatography (80% hexane/EtOAc) to give 5-methyl-6-nitroindane. To a mixture of 1.3 mL of HOAc and 7.3 mL of H2O heated to 90° C. is added 2.22 g of Fe. The mixture is heated until the gas evolution subsides. A solution of 1.9 g of 5-methyl-6-nitroindane (10.7 mmol) in 50 mL of EtOH is added dropwise and the reaction is heated to reflux for 30 minutes. The mixture is extracted twice with CH2Cl2. The combined organic layers are washed with saturated brine and dried over Na2SO4 and the solvents evaporated in vacuo to give a residue that is purified by column chromatography (75% hexane EtOAc) to give 6-methyl-5-aminoindane (also named 5-methyl-6-aminoindane).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[H-].[Na+].[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[CH3:32]>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (50.2 mg, 0.12 mmol, 1.0 equiv; Example 147) in anhydrous DMF (1 mL) was added sodium hydride (10.3 mg, 0.24 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and the reaction mixture stirred at rt. After 1 h, 4-bromo-butyric acid ethyl ester (545 mg, 400 μL, 2.80 mmol, 23.3 equiv; [CAS RN 2969-81-5]) was added and stirring continued under microwave heating to 120° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 5.5 mg (9%) of the title compound as a light yellow oil. MS (ISP): 532.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].O1CCCC1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:20][CH3:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:23]1([C:19](=[O:22])[CH:20]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)c1ccccc1)c1ccccc1
Yield: 77.4 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.022 g (0.1 mmol) of palladium (II) acetate, 0.721 g (7.5 mmol) of sodium-tert-butoxide and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.052 g (0.1 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 22° C. for 30 minutes. 0.563 g (5 mmol) of chlorobenzene was added, followed by stirring at 22° C. for 30 minutes. 0.738 g (5.5 mmol) of propiophenone was added, followed by stirring at 70° C. for 6 hours. After the completion of the reaction, 2.5 ml of water was added, followed by separation. The organic phase was purified by column chromatography to afford 0.814 g of 1,2-diphenyl-1-propanone (yield: 77 mol % based on chlorobenzene). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]([OH:21])=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:24]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH3:17])[C:7]2[CH2:6][CH2:5][O:4][C:3]([CH2:18][C:19]([OH:21])=[O:20])([CH2:1][CH3:2])[C:8]1=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c(n(Cc4ccccc4)c12)C(CC)(CC(=O)O)OCC3
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of (1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.4 g). After being heated at 50° C. for 2 hours, benzyl bromide (0.6 g, 3.5 mmol) was added and the solution was stirred for another 2 hours. It was quenched with ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.486 g (73%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.13 (m, 3H), 6.97 (d, 1H), 6.74 (d, 1H), 6.68 (t, 1H), 6.21 (d, 1H), 3.90 (s, 1H), 3.63 (m, 1H), 3.35 (td, 1H), 3.18 (d, 1H), 3.00 (d, 1H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1H), 1.85 (d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+) MS m/e=278 (MH+).
Reaction SMILES: [CH:1]1([C@H:7]([OH:22])[C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:9]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:27][NH2:28]>C1COCC1>[CH:1]1([C@H:7]([OH:22])[C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][NH:28][CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Crude (2S,3S)-3-cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropanal (3.22 g, 10.7 mmol, calculated according to theoretical yield) was dissolved in anhydrous THF (20 mL). The solution was cooled to 0° C. Acetic acid (5.5 mL, 90 mmol), methylamine solution (33% in EtOH, 5.0 mL, 40.0 mmol) and NaHB(OAc)3 (8.80 g, 40.0 mmol) were added sequentially and in single portions. The ice bath was removed and the mixture was stirred for 2 h at rt. The solvent was stripped and the crude 2-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione (6.45 g) was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-:28].[Na+]>C(O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@H:18]([CH2:19][CH2:20]2)[OH:28])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: [OH-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C

Procedure:
Feces (day 14) (25 mg) were weighed and placed in a test tube (15 mL) equipped with a screw cap, and an internal standard substance (5β-cholestane) (0.1 μmol) and a 90% ethanol solution containing 1N sodium hydroxide (1 mL) were added thereto. The mixture was heated at 80° C. by means of a block heater. One hour after, distilled water (0.5 mL) was added, and neutral sterols were taken through two rounds of extraction by use of petroleum ether (2.5 mL). The resultant extract was washed with distilled water (7.5 mL), dehydrated over sodium sulfate, and dried to solid under nitrogen gas flow. The recovered neutral sterols were trimethylsilylated, and analyzed through gas chromatography under the following conditions (Table 28).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([OH:28])=O)[CH2:21]4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:53][C:54]([F:65])([F:64])[O:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[CH:58][CH:57]=1>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([NH:61][CH2:60][C:59]5[CH:62]=[CH:63][C:56]([O:55][C:54]([F:53])([F:64])[F:65])=[CH:57][CH:58]=5)=[O:28])[CH2:21]4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)[C@H]1CCCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CCCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 23 %

Procedure:
To a solution of 3.3 (491 mg, 1.280 mmol) and TEA (535 μL, 3.84 mmol) in DCM (6402 μL) was added HATU (536 mg, 1.409 mmol) followed by 4-(trifluoromethoxy)benzylamine (Apollo Scientific Ltd., 215 μL 1.409 mmol) The reaction was stirred at room temperature for 40 hours. The reaction then was concentrated and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5 to 5% MeOH in DCM, to provide 3 as a light purple solid in 23% yield. 1H NMR (300 MHz, CD3OD) δ ppm 1.62 (br. s., 1H) 1.79-1.93 (m, 2H) 1.93-2.10 (m, 1H) 2.54 (br. s., 1H) 3.12 (br. s., 4H) 3.35-3.52 (m, 2H) 3.81 (br. s., 4H) 4.22-4.37 (m, 4H) 6.45 (d, J=7.31 Hz, 1H) 6.99 (d, J=8.62 Hz, 2H) 7.21 (d, J=8.04 Hz, 2H) 7.33 (t, J=8.40 Hz, 4H) 7.65 (d, J=7.31 Hz, 1H); M+H 557.24764.