Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:22])[CH2:20][SH:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][S:21][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1)[CH3:15]
Reactant: CC(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CSC(C)c1ccc(-c2ccccc2Cl)cc1

Procedure:
294 gm (1.17 mol) of 1-(2'-chloro-4-biphenylyl)-1-chloro-ethane and 149.2 gm (1.4 mol) of thioglycolic acid methyl ester were dissolved in 1 liter of dimethyl sulfoxide, and 194.3 gm (1.4 mol) of potassium carbonate were added to the solution in small portions, while stirring vigorously and cooling on ice water. After stirring the mixture for 4 hours, 3 liters of water were added. The reaction product was extracted with toluene, and after washing the extract with water and drying it over magnesium sulfate, the solvent was removed in vacuo. Yield: 359:0 gm (95.5% of theory). Rf -value: 0.6 on carrier 1 with cyclohexane/ethyl acetate=4:1.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][OH:26])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[O:26])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(C=O)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To DMSO (2.19 mL) in MeCl2 (40 mL) at −78° C. was added (COCl)2 (1.29 mL, ×mmol) dropwise. The reaction mixture was allowed to stir at −78° C. for 15 minutes and then 4-(2-Hydroxy-1-phenyl-ethyl)piperazine-1-carboxylic acid tert-butyl ester (364) (3.78 g, 12.34 mmol) in MeCl2 (8 mL) was added. The reaction mixture was allowed to stir at −78° C. for 1 h and then TEA (8.6 mL) amine added. The reaction mixture was allowed to stir at −78° C. for another 3 h and then allowed to warm to room temperature and stirred for 18 h. The reaction mixture is then quenched with sat. NH4Cl (55 mL). The desired product is extracted into EtOAc (100 mL). The organic phase is dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 30% EtOAc in hexanes) yielding 2.37 g (63%) pure product.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O>[Pd]>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2
Reactant: Nc1ccc2[nH]ncc2c1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc2[nH]ncc2c1N
Yield: 67.5 %

Procedure:
By referring to the Step 6 of Example 1, 4-nitro-5-aminoindazole (2.5 g, 14.0 mmol), Pd/C (0.25 g), were used to obtain a product (1.4 g, 65.5%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11](I)([F:16])[C:12]([F:15])([F:14])[F:13].CCCCCC>C(Cl)Cl>[C:2]1([C:1]([C:11]([F:16])([F:10])[C:12]([F:15])([F:14])[F:13])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: FC(F)(F)C(F)(F)I
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(c1ccccc1)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
Firstly, the starting material was prepared as follows: under protective gas, 35 g (0.25 mol) of benzoyl chloride in 150 ml of CH2Cl2 were initially introduced at about -20° C. into a round-bottomed flask. 67 g (0.27 mol) of pentafluoroethyl iodide were firstly condensed in and 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide were then metered in. The reaction mixture was subsequently stirred at 0° C. for a further 5 hours. After addition of the same volume of hexane to the reaction mixture, 2 phases formed. After phase separation, the lower phase was carefully extracted using hexane; the combined hexane phases were concentrated and distilled under reduced pressure. 20.8 g (58% yield) of pentafluoroethyl phenyl ketone of b.p. 76°-77° C./40 mbar were obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:19][CH:18]4[O:20][CH:15]([CH2:16][CH2:17]4)[CH2:14]3)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:14][CH:15]5[O:20][CH:18]([CH2:17][CH2:16]5)[CH2:19]4)[N:10]=3)=[CH:22][CH:23]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-fluoro phenylisocyanate (50 mg, 0.36 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 248; Yield 86 mg (86%); (M+H) 506.4
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]([CH3:28])=[C:19]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:20]=2)=[CH:12][CH:11]=1>>[CH3:28][C:18]1[O:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)=[N:20][C:19]=1[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OB(O)c1cccs1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 2-Thiophene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 339.1 (M+1)
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C[Si]([N:28]=[C:29]=[O:30])(C)C>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:29]([NH2:28])=[O:30])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: ClCCl
Product: NC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.053 g, 0.16 mmol) in DCM (1 mL) was added trimethylsilylisocyanate (1.6 mmol). The mixture was stirred at room temperature overnight and then more trimethylsilylisocyanate (1.6 mmol) was added and the mixture stirred for a further 5 hours. The solution was diluted with DCM (10 mL) and washed with water. The resulting organic solution was dried and the solvent evaporated. The resulting oil was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.014 g). LCMS m/z 376.12 [M+H]+ RT=8.89 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.25 (s, 1H), 6.9 (s, 1H), 4.7 (s, 2H), 4.6 (m, 1H), 4.1 (m, 2H), 3.8 (m, 1H), 3.2-2.7 (m, 4H), 2.1-1.05 (m, 17H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.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>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1OC
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[C:11]([F:17])[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)=[C:11]([F:17])[CH:10]=1
Reactant: OC1CCC1
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1COC1CCC1
Reaction time: 6 h

Procedure:
Sodium hydride (50% in oil; 1.63 g) was cautiously added to a solution of cyclobutanol (2.7 g) in DMF (12 ml). After gas evolution ceased, 4-bromo-1-bromomethyl-2-fluorobenzene (10 g) was added at 0° C. After 6 hours at room temperature, the mixture was cautiously hydrolyzed and then partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. 4-Bromo-1-cyclobutoxymethyl-2-fluorobenzene was obtained as crude product in this way.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].COC1C=CC(C[N:12]2[C:17]3=[N:18][N:19]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)=[CH:31][CH:30]=4)[C:20]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]3[C:15](=[O:41])[N:14]([CH3:42])[C:13]2=[O:43])=CC=1.C1(OC)C=CC=CC=1>ClCCCl>[CH3:42][N:14]1[C:15](=[O:41])[C:16]2=[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:19]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:33][CH:34]=3)[N:18]=[C:17]2[NH:12][C:13]1=[O:43]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n(Cc4ccc(-c5ccccn5)cc4)nc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccn4)cc3)c(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
AlCl3 (0.733 g, 5.50 mmol) is added to a solution of 7-(4-methoxybenzyl)-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.08 g, 1.98 mmol) and anisole (mL) in 1,2-dichloroethane (15 mL) under argon. The reaction mixture is stirred at room temperature overnight, and then quenched with water with cooling. The resulting suspension is treated with 20% NaOH (70 mL), and then extract with methylene chloride 5 times. The organic phase is combined and evaporated to dryness. The residue is further purified by chromatography to give 751 mg of pure product (Yield: 89%). MS (FAB) m/z 425.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[CH3:7][C:8]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1.O>CN(C)C=O>[Si:11]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([C:8]([CH3:10])([CH3:9])[CH3:7])([CH3:13])[CH3:12]
Reactant: COC(=O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CO[Si](C)(C)C(C)(C)C
Yield: 97876664 %

Procedure:
Methyl glycolate (0.776 ml, 0.905 g, 10.0 nmol) was added to a suspension of TBDMS-Cl (1.81 g, 12.0 mmol) and imidazole (1.7 g, 25.0 mmol) in dry dimethylformamide (DMF) (2.0 ml) at 0° C., under stirring. After 90 min stirring at RT, water (25 ml) was added, and the resulting mixture was extracted with ethyl ether (3×15 ml). The organic phases were combined, washed with water (3×15 ml), dried (Na2SO4) and evaporated to give methyl (t-butyldimethylsilyloxy)acetate (2.0 g, 100%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccncc2)cc1
Yield: 78 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 4-pyridineboronic acid, the expected product is obtained in the form of a cream powder with a yield of 78%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
Using the procedure described in Example 68, Part A, 4-methoxy-2-nitroaniline (1.0 g, 3.4 mmol) was reacted with 4-tert-butylbenzoyl chloride to yield 1.45 g (100%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:18])=[O:19])=[O:22])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1nnc(N)nc1C
Solvent: CC#N
Product: Cc1nnc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc1C
Reaction time: 6 h

Procedure:
To a dry, well stirred mixture of 12 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 100 ml of acetonitrile at ambient temperature and pressure was added 21 g of 2-chlorobenzenesulfonyl isocyanate. The mixture was stirred for 6 hours and the precipitated product removed by filtration. After washing with diethyl ether, the product melted at 142°-145°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with diethylamine
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>C1COCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:24][CH:25]=2)[CH:35]=1
Reactant: OC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of cyclopentanol (0.86 g) in anhydrous THF (8.6 mL), NaH (2.0 eq) was added in portions at 0° C., and then the mixture was stirred at 0° C. for 3 h. Then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (2.43 g, 0.5 eq) was added in portions. The mixture was stirred at room temperature overnight, whereupon TLC showed the reaction was complete. Then the reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4, and concentrated to a crude oil. The crude oil was purified by column chromatography (PE:EA=100:1) to obtain oil AC (1.0 g, yield ˜50%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].CS(C)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1c(CO)ccn1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide-pyridine complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give a white title compound (yield 5.27 g, 84%).
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCOCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
To a solution of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (71.2 g, 147 mmol) in 1,4-dioxane (400 mL) an aqueous solution of LiOH.H2O (220 mL, 2 M, 3 eq) was added. The resulting two phase mixture was stirred at 50° C. under N2 for 5 h. The reaction mixture was allowed to cool and the pH adjusted to 3-4 with 6 N HCl. The solvent was rotary evaporated and to the two phase aqueous/product mixture CH2Cl2 added. The layers were separated and the organics washed with H2O (2×300 mL). The combined aqueous phases were re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered and rotary evaporated. The dark brown oily residue was taken up in MeOH and the solvent evaporated under reduced pressure. The dark brown residue was taken up again in a minimum amount of MeOH and left in the fridge over 16 h. The precipitate was collected under suction, washing the solids with hexanes, and dried under high vacuum to afford the product (34.5 g, 51%) as an off-white solid. The filtrate containing product was concentrated to dryness to give a dark brown fluffy solid (33.6 g) which was processed further separately. LCMS m/z=458.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.57 (m, 4H), 1.93-1.81 (m, 2H), 2.16-1.97 (m, 3H), 2.38 (dd, J=15.2, 8.8 Hz, 1H), 2.80-2.62 (m, 4H), 3.32-3.23 (m, 1 H), 3.54-3.44 (m, 1H), 5.15 (s, 2H), 6.74 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.76-7.70 (m, 2H), 10.48 (s, 1H), 12.20 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([CH:7]=[C:8]([C:18]([O:20][CH2:21]C)=[O:19])[CH:9]([C:14]([F:17])([F:16])[F:15])[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([CH:7]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:14]([F:17])([F:15])[F:16])[O:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=Cc2ccc(OC)c(C)c2OC1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=Cc2ccc(O)c(C)c2OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
The ethyl 7-methoxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 3a, Step 2 (3.0 g, 9.49 mmole) was dissolved in methylene chloride (120 mL). The solution was chilled to −78° C. and BBr3 (94.9 mL, 1 M solution in CH2Cl2) was added slowly to the above solution. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was cooled to −78° C. and MeOH (30 mL) added in. After the solution was stirred at room temperature for 2 h, the reaction was evaporated to dryness to give a brownish solid having ca.90% purity. The crude product was further purified by passing through a silica plug to give a yellow solid (2.7 g, 80%): LCMS m/z 311.05 (M+Na). 1H NMR (acetone-d6/400 MHz) 9.11 (s, 1H), 7.75 (s, 1H), 7.11(d, 1H, J=8.4 Hz), 6.59 (d, 1H, J=8.4 Hz), 5.78 (q, 1H, J=6 Hz), 3.79 (s, 3H), 2.09(s, 3H).
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[C:27]=23)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:1])[C:27]=23)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Agent: O=C=O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
Gaseous NH3 is condensed into a cooled (dry ice/acetone) solution of 1-(3-benzyloxyphenyl)-3-tert-butyl-8-chloroimidazo[1,5-a]pyrazine (61.8 mg, 0.158 mmol) in iPrOH (2 mL) in a pressure tube until the volume is doubled, then the tube is sealed and heated to 110° C. (bath temp.) overnight. The seal has leaked during that time, LC indicates ≈50% conversion; therefore, ammonia is condensed in and the tube is heated as described before. The crude material is purified by preparative TLC (1000 μm silica gel layer, 20×20 cm plate), eluting once with 1% MeOH in CH2Cl2 and then three times with hexanes:EtOAc 3:1. One obtains the title compound as pale yellow solid, >95% pure by HPLC; 1H NMR (CDCl3, 400 MHz) δ 1.57 (s, 9H), 5.06 (brs, 2H), 5.14 (s, 2H), 6.99-7.04 (m, 2H), 7.22-7.26 (m, 2H), 7.31-7.42 (m, 4H), 7.44 (d, J=8.4 Hz, 2H), 7.46 (d, J=5.3 Hz, 1H). MS (ES+): m/z 373.1 (100) [MH+].