Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11]([CH3:13])=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:9]=[CH:8][C:10]([S:11]([C:13]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Product: Cc1ccc(Cl)cc1
Product: O=S(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The yield of p-chlorobenzaldehyde is 50%. Compared with the reaction with DMSO as sulphoxide, the yield is thus higher by a factor of 1.32. The difference between the ionisation potentials is 0.2 eV in this case.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Cc1ccc(CN)o1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Clc1ccc2c(I)cccc2n1
Product: Cc1ccc(CNc2ccc3c(Nc4ccc(S(C)(=O)=O)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=408.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 4-methylsulfonylaniline.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([OH:29])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1.[CH3:30]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([O:29][CH3:30])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1
Reactant: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 35.7 %

Procedure:
Sodium hydride (60% in oil, 50.8 mg, 1.27 mmol) was added to a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (250 mg, 1.06 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After stirring 5 min, methyl iodide (226 mg, 1.59 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (166 mg, 0.378 mmol, 36%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.C[CH2:49][O:50]CC>CC(N(C)C)=O>[CH3:1][N:2]([C:49](=[O:50])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Ic1ccccc1
Reactant: CNC(=O)c1ccccc1
Reactant: CCOCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 115 °C
Reaction time: 23 h
Yield: 7 %

Procedure:
A pressure vessel (Fisher-Porter bottle) equipped with a Teflon coated stir bar, a gas inlet, a pressure gauge, and a pressure release valve was charged with N-methylbenzamide (242 mg, 1.79 mmol), iodobenzene (200 μl, 1.29 mmol), PdCl2L2 (76 mg, 0.107 mmol), triphenylphosphine (56 mg, 0.214 mmol) and DMAc (3.4 ml) and heated (115° C.) under one atmosphere of CO until the reactants had dissolved. DBU (320 μl, 2.14 mmol) was then introduced into the reaction mixture and the reactor charged to 40 psi with CO. After 23 hours, the reactor was cooled to room temperature, depressurized, and the reaction mixture diluted (50 ml) with ether and extracted (3×50 ml) with water. The ether layer was dried over MgSO4 and concentrated to give a red oil which was chromatographed on silica gel (2:1, hexane:ethyl acetate) to give 30 mg product (7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].I[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:12]([CH3:14])[CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)cc(O)cc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(OC(C)C)cc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A mixture of 3,5-dibromo-4-methyl-phenol (11.2 g, 42.1 mmol), 2-iodopropane (8.50 mL, 85.0 mmol), potassium carbonate (17.5 g, 126 mmol), and anhydrous DMF (100 mL) was stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ether (300 mL) and water (300 mL). The organic phase was separated, washed with brine (2×300 mL), dried over sodium sulfate, and concentrated under vacuum to give 1,3-dibromo-5-isopropoxy-2-methyl-benzene (Cpd A, 12.8 g, 99% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.[NH2:25][CH2:26][CH:27]([OH:30])[CH2:28][NH2:29].[H][H]>C(O)C.[Pt]=O>[NH2:25][CH2:26][CH:27]([OH:30])[CH2:28][NH:29][CH:11]([CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2)[CH2:10][CH2:9][CH:3]1[C:2]([CH3:24])([CH3:1])[CH:7]2[CH2:8][CH:4]1[CH2:5][CH2:6]2
Reactant: NCC(O)CN
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCC(O)CN

Procedure:
A solution of 1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentanone (13.2 g., 0.04 mole) in 50 cc of anhydrous ethanol is added dropwise over about 20 minutes to a stirred solution of 1,3-diamino-2-hydroxypropane (25 g., 0.27 mole) in 200 cc of ethanol. The resulting mixture is then heated at reflux for about two hours, allowed to cool, 1.0 g. platinum oxide added, and the mixture reduced under a 40 psi hydrogen atmosphere until hydrogen uptake ceases. The mixture is then filtered from the catalyst, concentrated in vacuo to remove the ethanol, the oily residue taken up in ether (250 cc.), washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product 1-amino-3-[1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentylamino]-2-propanol as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:17]([C:18]1[CH:19]=[CH:20][C:21]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:22][CH:23]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: Ic1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Temperature: 110 °C

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 1-iodo-4-phenoxy-benzene (Aldrich, 296 mg, 1 mmol), Cul (Strem Chemicals, 19 mg, 0.1 mmol), 1,10-phenanthroline (Aldrich, 36 mg, 0.2 mmol), and Cs2CO3 (660 mg, 2.0 mmol) in toluene (anhydrous, Aldrich, 10 mL) and heated at 110° C. for two days. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×10 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:1, Rf. 0.20) as oil (220 mg, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 2.70–3.10 (m, 5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt, J=7.5, 1.0 Hz, 1H), 7.20–7.41 (m, 2H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]#[N:21])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(=O)([O-])[O-:23].[Na+].[Na+]>S(=O)(=O)(O)O.O.C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]([NH2:21])=[O:23])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOP(=O)(Cc1cc(C#N)nc2ccccc12)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cc1cc(C(N)=O)nc2ccccc12)OCC
Temperature: 0 °C

Procedure:
A solution of 5.9 g of 4-(diethylphosphonomethyl)-2-cyanoquinoline in 24 ml of concentrated sulfuric acid is heated at 80° for 5 minutes, cooled to 0° and added slowly to an ice-cooled mixture of 50 g of sodium carbonate in 50 ml of water and 100 ml of methylene chloride. The organic layer is separated, dried over sodium sulfate and evaporated to dryness to yield 4-(diethylphosphonomethyl)-quinoline-2-carboxamide.
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:32])[CH3:31])[CH:25]=2)(=[O:23])=[O:22])=[CH:12][C:11]=1[C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:72]Br.CC(C)=O>O1CCOCC1.CCCCCC>[C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:32])[CH2:31][Br:72])[CH:25]=2)(=[O:23])=[O:22])=[CH:12][C:11]=1[C:33]([N:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[O:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cccc(C(C)=O)c2)c2ccccc2c1OC(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cccc(C(=O)CBr)c2)c2ccccc2c1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of 15.7 g (15.7 mmol) of 1-benzoyloxy-4-(3-acetylbenzenesulfonamido)-N,N-dioctadecyl-2-naphthamide in 150 ml of dioxane was treated with 2.51 g (15.7 mmoles) of bromine at 40° to 45° C. The reaction was held for one hour at this temperature, during which time the bromine color discharged. Analysis by TLC (25 percent acetone in hexane) indicated a complete reaction and only one main product was observed. The solution was drowned to ice water and the resulting mixture was extracted with chloroform. The chloroform extracts were combined and washed well with water, dried (MgSO4), and stripped to give 15 g (89 percent) of an oil which was used without further purification.
Reaction SMILES: [C:1](OC)([CH3:4])([CH3:3])[CH3:2].[C:7]1([CH3:41])[CH:12]=[CH:11][C:10]([C:13]2[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=4)[CH2:16][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1.[CH2:42]([Li])[CH2:43][CH2:44][CH3:45].Cl>C(OCC)C.CCCCCC>[CH2:2]([C:45](=[C:24]1[C:23]2[C:15]([CH:16]=[C:17]3[C:22]=2[CH:21]=[C:20]([C:30]([CH3:31])([CH3:32])[CH3:33])[C:19]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[CH:18]3)=[C:14]([CH:17]2[CH:22]=[CH:23][CH:15]=[CH:16]2)[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:41])=[CH:8][CH:9]=2)=[C:25]1[C:26]([CH3:29])([CH3:27])[CH3:28])[CH2:44][C:43]1[CH:42]=[CH:12][CH:7]=[CH:8][CH:9]=1)[C:1]1[CH:4]=[CH:11][CH:10]=[CH:13][CH:3]=1
Reactant: COC(C)(C)C
Reactant: Cc1ccc(-c2cc3c(cc2C(C)(C)C)-c2cc(C(C)(C)C)c(-c4ccc(C)cc4)cc2C3)cc1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(-c2cc3c(cc2C(C)(C)C)=c2c(c(C4C=CC=C4)c(-c4ccc(C)cc4)c(C(C)(C)C)c2=C(Cc2ccccc2)Cc2ccccc2)C=3)cc1
Yield: 51 %

Procedure:
Under a nitrogen atmosphere, 100 mL of dehydrated tert-butylmethylether was added to 1.30 g (2.84 mmol) of 2,7-di(p-tolyl)-3,6-ditert-butyl-fluorene, and the mixture was stirred. This solution was cooled in an ice bath, and 2.10 mL (3.36 mmol) of a 1.60 mol/L hexane solution of n-butyllithium was added. The solution was stirred at room temperature for 21 hours. To the yellowy-black suspension obtained, 0.808 g (3.12 mmol) of 6,6-dibenzofulvene synthesized in Synthesis Example 1-1(iii) was added. Subsequently, the mixture was heated to reflux for 19 hours. Subsequently, 30 mL of 1N hydrochloric acid was added to the red-brown solution obtained to terminate the reaction. Then, 100 mL of diethylether was added to perform a liquid-liquid phase separation, and the soluble fraction was extracted. This organic layer was washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and then dried over magnesium sulfate. The solvent was solvent was distilled off, and the residue was subjected to separation by column chromatography. The whitish yellow powder obtained was washed once with 10 mL of cold hexane, three times with 5 mL of cold ethanol, and 3 times with 2 mL of cold hexane to obtain a target product as a white powder (yield 1.04 g (51%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6](O)[C:5]=2[CH:4]=[N:3]1.[I:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[NH:15][N:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[I:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=3)[N:14]=1
Reactant: Cn1ncc2c1CCCC2O
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc2c1CCCC2n1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.7 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (400 mg, 2.63 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (684 mg, 2.63 mmol) and Ph3P (1.03 g, 3.94 mmol) in THF (40 mL) was added DIAD (798 mg, 3.94 mmol) dropwise at 0° C. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was extracted with EA, the combined the organic layers were washed with brine and dried over anhydrous Na2SO4. The volatiles were concentrated in vacuo and the residue was purified by silica gel chromatography (DCM/methanol=40/1 v/v %) to give 3-iodo-1-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 8%). MS-ESI (m/z): 396 (M+1)+ (Acq Method: 10-80AB_2 min_220 &254.1 cm; Rt: 0.82 min)
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][C@@H:5]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([CH2:18][C:19]([O:21]C)=[O:20])[C@H:13]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[OH-:35].[K+].Cl.[CH3:38][OH:39]>>[CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][C@@H:5]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([CH2:18][C:19]([OH:21])=[O:20])[C@H:13]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=1)[CH2:6][CH2:7][C:8]([F:9])([F:10])[F:11].[C:38]([OH:39])([C:8]([F:11])([F:10])[F:9])=[O:35]
Reactant: CO
Reactant: COC(=O)C[C@H]1CCCN([C@H](CCC(C)(C)C)CCC(F)(F)F)[C@@H]1c1ccc(C(F)(F)F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CC(C)(C)CC[C@H](CCC(F)(F)F)N1CCC[C@H](CC(=O)O)[C@H]1c1ccc(C(F)(F)F)cc1
Product: O=C(O)C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of methyl {(2S,3R)-1-[(1R)-4,4-dimethyl-1-(3,3,3-trifluoropropyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl}acetate (3.9 g) in methanol (50 mL) was treated with 1M potassium hydroxide in methanol (25 mL, 25.0 mmol) was heated to 60° C. for 16 hours. The reaction was treated with 25 mL 1M HCl and partitioned between water and ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The reaction was purified by reverse phase chromatography (35-100% acetonitrile/water) to give {(2S,3R)-1-[(1R)-4,4-dimethyl-1-(3,3,3-trifluoropropyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl}acetic acid as its TFA salt. This salt was taken up in ethyl acetate and treated with 10 mL concentrated HCl and stirred vigorously for 24 hours. The solution was evaporated in vacuo to give exclusively the HCl salt. 1H NMR (600 MHz, CD3OD: δ 7.80 (bm, 4H), 4.65 (bm, 1H), 3.69 (bm, 1H), 3.22 (bm, 1H), 2.69 (bs, 2H), 2.24 (m, 1H), 2.12 (m, 4H), 2.04 (d, J=8.2 Hz, 1H), 2.01 (d, J=8.2 Hz, 1H), 1.91 (m, 3H), 1.66 (m, 1H), 1.51 (m, 1H), 1.13 (m, 1H), 0.92 (s, 9H), 0.74 (td, J=12.6, 3.8 Hz, 1H); LC/MS (EIMS, M+H)=482.1.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)=[O:5])[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O
Reactant: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CS(=O)Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Sodium perborate tetrahydrate (42 mg, 0.27 mmol) was added as a solid to a stirred solution of (2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionic acid (150 mg, 0.27 mmol), in acetic acid (5 mL) at 40° C. This solution was stirred at 40° C. for 1 hour (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a 1:1 mix of diastereoisomers as a white solid (144 mg, 93%): Rf 0.25 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, dd, J=8, 1 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.87 (2H, d, J=9 Hz, Ar—H), 7.78 (4H, m, Ar—H), 7.52 (2H, m, Ar—H), 7.44 (4H, m, Ar—H, NH), 4.39 (1H, m, CHN), 4.05-4.27 (2H, m, PhCH2), 3.04 (1H, m, CHHCHN), 2.92 (1H, m, CHHCHN), 1.39 and 1.37 (both 4.5H, s, CMe3 diastereomers); ESI-LCMS e/z calcd for C33H31NO6S 569.675, found 570 (M+H)+, 592 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][CH2:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Reactant: NCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)NCCc1cccnc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 7 mg (0.055 mmol) of 3-aminoethylpyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:21])[C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>C(O)CCC>[C@@H:32]1([NH:31][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:21])[C@H:9]3[C@@H:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]4[C@@H:11]([CH2:19][OH:20])[CH2:10]3)[CH:3]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1cc(N[C@H]2CCc3ccccc32)ncn1)[C@@H]1C[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Temperature: 200 °C
Yield: 24.1 %

Procedure:
{(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (130 mg, 0.41 mmol) was weighed into a microwave reaction tube and dissolved in 1-butanol (1.50 mL). To this solution was added N,N-diisopropylethylamine (0.22 mL, 1.24 mmol) and (S)-(+)-1-aminoindan (0.16 mL, 1.24 mmol) and the mixture was heated in a sealed tube under microwave irradiation at 200° C. for 4 h. The reaction mixture was concentrated under vacuum, and the residue was purified via silica gel column chromatography eluting with a gradient of 2 to 5% methanol in DCM to afford the title compound (40.5 mg, 24%) as a colorless oil. LC/MS: Rt=1.49 min, ES+ 411.5 (AA standard).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[C:5]2=[C:6]([OH:24])[CH:7]=[CH:8][CH:9]=3)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]#[N:34]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:32][C:33]#[N:34])[C:5]2=3)[CH:14]=1
Reactant: N#CCBr
Reactant: Cc1cc2c3c(c1)c1c(O)cccc1n3C(c1ccccc1)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 45.5 %

Procedure:
To a mixture of 5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (1.3 g, 4.12 mmol) in DMF (15 mL) is added potassium carbonate (2.8 g, 20.6 mmol) and bromoacetonitrile (1.4 mL, 20.6 mmol). The mixture is heated at 85° C. for 1.5 h. The mixture is cooled and partitioned between water and CH2Cl2. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (100 g silica gel) using ethyl acetate/hexanes (20/80) eluent gave 0.665 g (46%) of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.