Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:16])[CH3:15])=[O:31]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (60 mg, 0.28 mmol, example 23, intermediate a) and DIPEA (97 μL, 0.56 mmol) was added 3,5-dichlorobenzoyl chloride (87 mg, 0.42 mmol, CAS RN 2905-62-6) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound (43 mg, 40%). MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23](Br)[N:22]=[N:21]4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[CH2:29]([OH:32])[C:30]#[CH:31]>CN1CCCC1=O.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu](I)I>[O:1]=[S:2]1(=[O:28])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([C:31]#[C:30][CH2:29][OH:32])[N:22]=[N:21]4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1
Reactant: O=C1O[C@@H](Cn2cc(Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: C#CCO
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1O[C@@H](Cn2cc(C#CCO)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 90 °C
Yield: 12.1 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-bromo-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 36) (235 mg, 0.5 mmol), propargyl alcohol (42 mg, 0.75 mmol), tetrakis(triphenylphosphine)palladium (0) (29 mg, 5 mol %) and copper iodide (5 mg, 5 mol %) were mixed in N-methylpyrrolidone/triethylamine (5 ml, 5:1). The reaction mixture was flushed with nitrogen and heated to 90° C. for 48 hours. The reaction mixture was filtered and extracted with ethyl acetate/water, the organic phase was concentrated and purified by flash chromatography on silica gel with 5% of methanol in dichloromethane to give the title product (27 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][OH:13])[O:8][N:7]=1)=[O:5].[OH:19]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][C:12]([OH:19])=[O:13])[O:8][N:7]=1)=[O:5]
Reactant: O=C(c1cc(CCO)on1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2Cl)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 12.8 g of 2-[3-(2,4-dichlorobenzoyl)-isoxazol-5-yl]ethanol and a few crystals of tetra-n-butylammonium hydrogen sulfate in 1000 ml of CH2Cl2 was added 150 ml of 9M H2SO4. To this was added 13.2 g of pulverized K2Cr2O7 and the mixture was stirred at room temperature for 1 hour. The organic phase was separated from the aqueous phase and washed with water. The acid product was extracted from the organic phase using 40 ml of 4% NaHCO3. The alkaline solution was washed with CH2Cl2 several times, until all the neutral impurities were removed, and the solution was then acidified slowly with 5% HCl until all the acid precipitated. The solid was filtered, washed with water, and dried to yield 3.9 g of a powder. Recrystallization from 100 ml of 50% toluene/hexane gave 3.5 g (26%) of crystals, m.p. 108°-109° .
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][SH:29]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN(C)CCS
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(SCCN(C)C)s2)c(C(=O)C2CCCC2)c1
Yield: 30.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(2-dimethylamino-ethylsulfanyl)-thiazol-2-yl]-urea (130 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-dimethylamino-ethanethiol (210 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:43][C:44](O)=[O:45])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:44](=[O:45])[CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:14]3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[CH:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCCC3)CC21
Yield: 77.8 %

Procedure:
By working according to the procedure of Example 1, starting from 0.62 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol and 0.40 g of 2-(1-pyrrolidinyl)phenylacetic acid, 0.70 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-(1-pyrrolidinyl)phenyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 236° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[C:14](=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=4)[CH:15]=3)=[CH:10][N:5]2[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1([C:46]2[S:47][CH:48]=[C:49]([CH2:51]O)[N:50]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:51][C:49]5[N:50]=[C:46]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[S:47][CH:48]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COc1nn2cc(-c3cc4c(O)cccc4o3)nc2s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cccc4o3)nc2s1
Temperature: 2 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 38G, 0.100 g, 0.349 mmol), triphenylphosphine (0.165 g, 0.627 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.080 g, 0.418 mmol) in a 50 ml flask was maintained under vacuum for 10 min and then purged with nitrogen. Dry tetrahydrofuran (10 mL) was added and the resulting mixture was slightly warmed and maintained in an ultrasonic bath for 5 min. The cooled mixture (still heterogeneous) was treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.113 g, 0.558 mmol) in tetrahydrofuran (2 mL) added dropwise over 1 h. The mixture was then stirred at 2° C. for 4 h. The clear reaction mixture was quenched by the addition of dichloromethane (100 mL) and saturated sodium bicarbonate (10 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel (2.5×12 cm, elution dichloromethane-ethyl acetate 0-3%) followed by crystallization of the desired fraction from ethyl acetate (8 mL) gave 0.028 g (24% yield) of the title material as a white solid. LC (Method A): 2.426 min. HRMS (ESI) calcd for C23H17N4O3S2 [M+H]+ m/z 461.0737, found 461.0926. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.22 (s, 3H), 5.45 (d, J=0.78 Hz, 2H), 6.80 (dd, J=7.04, 1.57 Hz, 1H), 7.15-7.21 (m, 2H), 7.22 (s, 1H), 7.38 (s, 1H), 7.42-7.51 (m, 3H), 7.92 (s, 1H), 7.95-8.03 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[C:13]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=[CH:11]3)=[CH:7][C:6]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:5][CH:4]=2.[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:35]1([C:41]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:41][C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:3]4[C:8]([C:9]([C:38]5[CH:39]=[CH:40][C:35]([CH:41]=[C:41]([C:3]6[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=6)[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:36][CH:37]=5)=[C:10]5[C:11]=3[CH:12]=[C:13]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:15]5)=[CH:7][C:6]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:5][CH:4]=4)=[CH:37][CH:36]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCC(CC)COc1ccc2c(Br)c3cc(OCC(CC)CCCC)ccc3c(Br)c2c1
Reactant: Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc2c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3cc(OCC(CC)CCCC)ccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c2c1
Temperature: 0 °C
Yield: 2374.6 %

Procedure:
Into a 500 ml flask equipped with a condenser, 0.6 g (1 mmole) of 9,10-dibromo-2,6-di(2-ethylhexyloxy)anthracene, 0.04 g (5% by mole) of dichlorobis(triphenylphosphine)palladium, 0.1 ml (1 M; 0.1 mmole) of a toluene solution of diusobutylaluminum hydride and 10 ml of THF were placed under a stream of argon. After the Grignard reagent prepared above was added dropwise to the obtained solution at the room temperature, the resultant mixture was heated under stirring for one night. After the reaction was completed, the reaction solution was cooled with ice water. The formed crystals were separated by filtration and washed with 50 ml of methanol and 50 ml of acetone successively, and 0.56 g of a yellow powder was obtained. The obtained yellow powder was identified to be Compound (A1) by the measurements in accordance with NMR, IR and the filed desorption mass spectroscopy (FD-MS) (the yield: 60%).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[CH3:14][O:15][CH:16]([O:27][CH3:28])[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>CO>[I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]=[CH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([O:27][CH3:28])[O:15][CH3:14])=[CH:26][CH:25]=1
Reactant: COC(COc1ccc(C=O)cc1)OC
Reactant: Cc1ccc2ccccc2[n+]1C
Agent: [I-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(COc1ccc(C=Cc2ccc3ccccc3[n+]2C)cc1)OC
Yield: 70.2 %

Procedure:
In 20 ml of methanol, 4.28 g of 1,2-dimethylquinolinium iodide and 3.47 g of p-(2,2-dimethoxyethoxy)benzaldehyde were dissolved. The resultant solution, with 0.3 ml of piperidine added thereto, was refluxed for seven hours. The solution was left to cool. The crystals which consequently deposited were collected through filtration and then washed thoroughly with acetone. Consequently, there was obtained 5.03 g of 1-methyl-2-[p-(2,2-dimethoxyethoxy)-styryl]quinolinium iodide which boiled at 209°~212° C. This product in water showed absorption bands (λmax) at 224, 255, 307 and 399 nm. The infrared absorption spectrum (KBr) showed peaks at 1610, 1590, 1572, 1516, 1240, 1180, 1130, 1068, 985, 830, 780 and 760 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:28])[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([OH:27])[CH:20]=3)[CH2:13][CH2:12]2)[CH:7]=[C:6]([O:29][CH2:30][CH3:31])[C:5]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:19]3[CH:20]=[C:21]([O:27][S:40]([CH3:39])(=[O:42])=[O:41])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:28])[CH2:13][CH2:12]2)[CH:7]=[C:6]([O:29][CH2:30][CH3:31])[C:5]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 72a), N-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 259) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 601.3 (MH+).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>O>[Na+:5].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1
Reactant: O=S([O-])[O-]
Reactant: Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To a solution of sodium sulfite (14.3 g 113 mmol) in water (60 mL) was added 4-methylbenzyl chloride (15.0 mL, 113 mmol). The mixture was stirred under reflux for 12 hours, and cooled to rt. The precipitate was collected by filtration, and washed with water and ether to give 4-methylphenylmethanesulfonic acid sodium salt (12.5 g, 60 mmol, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([S:10][C:11]1[N:12]=[C:13]([NH:22][C@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])[C:14]2[S:19][C:18]([O:20]C)=[N:17][C:15]=2[N:16]=1)[CH3:9]>C(=O)(O)[O-].[Na+].O>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([S:10][C:11]1[N:12]=[C:13]([NH:22][C@@H:23]([CH2:24][OH:25])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:14]2[S:19][C:18](=[O:20])[NH:17][C:15]=2[N:16]=1)[CH3:9]
Reactant: COc1nc2nc(SC(C)c3ccncc3F)nc(N[C@@H](CO)CC(C)C)c2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2ccncc2F)nc2[nH]c(=O)sc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The title compound was prepared starting from (2R)-2-[(5-{[1-(3-fluoropyridin-4-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol from the previous step using General method D, except that the reaction mixture was stirred at 50° C. for 2 h. After complete reaction the reaction mixture was diluted with sat. sodium bicarbonate aq. and water (1:1) and extracted with DCM (three times). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The product was purified by flash column chromatography (eluent heptane:ethyl acetate gradient) to yield the title compound as a mixture of diastereomers (194 mg).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:32]Br>CCO.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:32][C:11]1[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:30])[F:31])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][CH2:17][CH:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:19][CH2:20]1
Reactant: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol (699 mg, 1.49 mmol) in EtOH (10 mL) was added bromine (77 μL, 1.49 mmol) and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with a saturated aqueous sodium thiosulfate (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated and washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (12 g of silica gel, 10 to 25% EtOAc in hexanes) to provide 2-(3-bromo-4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (567 mg) as a mixture of two enantiomers.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=2)[CH:8]=[N:9]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cn[nH]c2c1
Yield: 94 %

Procedure:
A mixture of 6-nitro-1H-indazole (25 g, 0.153 mmol, commercially available) and 10% Pd/C (2.0 g) in MeOH was stirred under H2 (1 atm) overnight. After filtration, the filtrate was concentrated to yield 1H-indazol-6-ylamine (18.5 g, 94% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 12.20 (br s, 1H), 7.70 (s, 1H), 7.35 (d, J=5.4 Hz, 1H), 6.49-6.44 (m, 2H), 5.17 (brs, 2H). MS (ESI) m/z: 134 (M+H+).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[CH:12]=1)=[O:10])C1C=CC=CC=1.[OH-].[K+]>O.C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:9]([OH:10])=[O:8])[CH:20]=[CH:19]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 6-benzyloxy -naphthalene-2-carboxylic acid benzyl ester (52) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature and quenched with hydrochloric acid (5%), filtered resulted white solid, washed with water, and dried under vacuum to 6-benzyloxy-naphthalene-2-carboxylic acid (53) as a white solid (81%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(C)(C)C)ccc3n2CC(O)c2ccncc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.1 mmol) in DMF (6 mL) was added sodium hydride (495 mg, 12.3 mmol) under nitrogen at 0° C. and stirred for 10 min. A solution of 4-(oxiran-2-yl)pyridine (898 mg, 7.4 mmol) in DMF (2 mL) was added dropwise into the reaction mixture at RT and stirred for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction mass was poured in ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized with hexane to yield 2-(8-tert-butyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.7 (d, 2H), 7.3 (s, 1H), 7.2 (d, 1H), 7.19 (d, 2H), 7.17 (d, 1H), 4.7 (t, 1H), 4.0 (d, 2H), 3.5 (dd, 2H), 2.82 (m, 1H), 2.7 (m, 2H), 2.58 (m, 1H), 2.4 (s, 3H), 1.4 (s, 9H). Separation by chiral HPLC provides enantiomers II-68a-b.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:13])[CH2:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[NH:12][C:10](=[O:11])[CH2:9][C@@H:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H](CC(N)=O)Nc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccccc1
Temperature: -10 °C
Yield: 82 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (S)-3-phenylamino-butyramide (3.25 g, 0.018 mmol) in THF (65 mL) and the mixture was cooled to −10° C. Benzyl chloroformate (3.12 mL, 0.022 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (18 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction (starting material gone by TLC) was quenched by adding EtOAc (65 mL) and 1.0 M hydrochloric acid (10 mL). The aqueous phase was then basified with 1N NaOH. The aqueous phase was extracted 3× EtOAc. The organics were collected together and with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography using a Biotage system (10% EtOAc/90% hexane to 20% EtOAc/80% Hexane) afforded the title compound in 82% yield.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15]Cl>C1COCC1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:2]([CH2:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: ClCc1cccs1
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccs1)(Cc1cccs1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.3 %

Procedure:
87.8 g of dimethyl malonate and 41.0 g of potassium t-butylate are dissolved in 1.1 l of THF (anhydrous) while cooling in ice, and, under argon, 44.1 g of 2-thienylmethylchloride in 500 ml of THF are added dropwise. The mixture is stirred at R.T. for 3 h, the KCL is removed by filtration, the solvent is removed in vacuo, and the residue is chromatographed. 33.8 g of the title compound (I) are obtained as a colorless oil, in addition to 8.8 g of dimethyl bis-(2-thienylmethyl)malonate (II)
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1)[CH3:19]>CN(C)C=O>[CH2:18]([C:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=2)[CH2:22][CH:21]=1)[CH3:19]
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: CCC1=CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1=CCN(Cc2cnc(C)nc2N)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A suspension of 0.95 g (0.0050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 13 ml of dimethylformamide was treated with 3.5 ml (0.025 mol) of triethylamine and 1.16 g (0.010) of 4-ethyl-1,2,3,6-tetrahydropyridine and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.60 g (52%) of 5-(4-ethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-pyrimidin-4-ylamine were obtained as a beige solid; m.p. 75°-76°.