Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCCC1CC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCCCC1CC1)C(=O)OCC

Procedure:
2.5 g of 8-cyclopropyl-2-methyleneoctanoic acid ethyl ester, in the form of a yellowish oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 4.53 g of (6-cyclopropylhexyl)-malonic acid ethyl ester 0.64 g of paraformaldehyde, 4 ml of pyridine and 0.2 ml of piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:22][CH:21]([O:23][Si](C(C)(C)C)(C)C)[CH2:20]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(N1CCc2ccc(Cl)c(N3CC(O)C3)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
Under nitrogen mix 7-chloro-6-[3-(tert-butyldimethyl-silanyloxy)-azetidin-1-yl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (594 mg, 1.29 mmol), 1 N tetrabutylammonium fluoride solution in THF (2.04 mL, 2.04 mmol), glacial acetic acid (0.2 mL, 3.33 mmol), 4 Å molecular sieve (650 mg) in anhydrous THF (18 mL). Stir at RT for 3 days. After the first day add more 1 N tetrabutylammonium fluoride solution in THF (2.04 mL, 2.04 mmol) and glacial acetic acid (0.2 mL, 3.33 mmol). After the second day add more 1 N tetrabutylammonium fluoride solution in THF (2.04 mL, 2.04 mmol) and glacial acetic acid (0.2 mL, 3.33 mmol). Stop the reaction on the third day. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution and 0.1 N NaOH. Extract the aqueous layer three times with EtOAc. Combine the EtOAc fractions, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 EtOAc:hexanes) to give the title compound (325 mg, 72%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]2[C:31](=[O:32])[C:30]3[CH:33]=[CH:34][CH:35]=[C:28]4[C:29]=3[C:24](=[CH:25][CH:26]=[CH:27]4)[C:23]2=[O:36])[CH2:16][CH2:15]1)=[O:4]>[OH-].[K+]>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][N:22]2[C:23](=[O:36])[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:29]=3[C:30](=[CH:33][CH:34]=[CH:35]4)[C:31]2=[O:32])[CH2:18][CH2:19]1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1

Procedure:
0.8 g of 2-[2-(4-(5-methoxycarbonyl-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione[obtainable according to Example 1] is heated with 100 ml of 2N ethanolic KOH for 0.5 hours and worked up in the customary manner, and 2-[2-(4-(5-carboxy-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.OCC(CO)O.S(=O)(=O)(O)O.[OH-].[NH4+].C>O.C(O)(=O)C>[N:1]1[C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=2[CH:15]=[CH:14][CH:19]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc2ncccc12
Temperature: 50 °C
Yield: 35.2 %

Procedure:
To a solution containing 15 g (0.1 mol) of m-aminobenzoic acid, 27 g (0.13 mol) of m-nitrobenzene sulfonate and 25 g (0.4 mol) of glycerol, was added 125 g of 70% sulfuric acid. The resultant reaction mixture was refluxed for about 2.5 hours, diluted with 125 mL of water, basified to pH 9 using ammonium hydroxide, stirred overnight with 5 g of charcoal, and then filtered. The filtrate was then boiled with 5 g charcoal, filtered, and then cooled to 50° C., acidified to pH 5 with glacial acetic acid (15 mL), and filtered to provide a brown solid. This solid was boiled in 300 mL of water containing 10 mL of acetic acid and hot filtered to provide crude material. This material was purified using recrystallization from boiling acetic acid to provide 6.1 g of a pale brown solid.
Reaction SMILES: [Na:1].COC1OCC(C[O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1([CH2:40][CH2:41]O)[O:39][CH2:38][C:35]2([CH2:37][CH2:36]2)[CH2:34][O:33]1>>[Na:1].[CH3:30][C:13]1[C:14]([CH2:18][S:19]([C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[O:20])=[N:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:41][CH2:40][C:32]1([CH3:31])[O:33][CH2:34][C:35]2([CH2:37][CH2:36]2)[CH2:38][O:39]1
Reactant: CC1(CCO)OCC2(CC2)CO1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCC3(CC3)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 5.5 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(6-methyl-5,7-dioxaspiro[2.5]oct-6-yl)ethanol obtained in the step (35a) to obtain the title compound (163 mg, total yield: 5.5%) as a light yellow solid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Br[C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=1>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Reactant: Fc1cc(Br)cc(F)c1F
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
Using 4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanone and 1-bromo-3,4,5-trifluorobenzene as starting raw materials, 1-(trans-4-propylcyclohexyl)-2-[trans-4-(3,4,5-trifluorophenyl)cyclohexyl]ethane was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14][CH3:15])=[C:6]([NH2:16])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[NH2:16][C:6]1[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(C(C)=O)cc(N)c1OC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(C(C)O)cc(N)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a 0° C. solution of methyl 6-acetyl-4-amino-3-methoxypicolinate (0.75 g, 3.35 mmol) in MeOH (11.15 ml) was added sodium borohydride (0.127 g, 3.35 mmol) by portion. The reaction mixture was stirred at room temperature (TLC monitoring). After 2 h, the reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc (2×) and CH2Cl2 (1×). The combined organic layers were dried over MgSO4, filtered, concentrated and dried in vacuo to afford methyl 4-amino-6-(1-hydroxyethyl)-3-methoxypicolinate (0.548 g, 2.422 mmol, 72.4% yield) as a brown oil, which was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 6.72 (s, 1H), 4.76 (q, J=6.4 Hz, 1H), 4.52 (s, 2H), 3.96 (s, 3H), 3.94 (s, 1H), 3.86 (s, 3H), 1.45 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH3:2].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:6]=[C:7]([C:11]([F:12])([F:14])[F:13])[CH:8]=[CH:9][C:10]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1cccc(C(F)(F)F)c1
Product: CCNC(=O)c1cc(C(F)(F)F)ccc1[Si](C)(C)C

Procedure:
This amide was reacted with TMSCl (1.3 eq) as in Example 221 to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from pentane (-78° C.) to afford 0.14 g (5%) of the title compound as a white solid. m.p. 101°-102° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C@@:15]1([C:42]([F:45])([F:44])[F:43])[CH2:39][C@H:19]2[CH2:20][CH2:21][CH2:22][C:23]3[C:24](=[CH:25][C:26]4[CH:27]=[N:28][N:29]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[C:30]=4[CH:31]=3)[C@:18]2([C:40]#[N:41])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC.C1COCC1>[CH2:7]([O:14][C@@:15]1([C:42]([F:44])([F:45])[F:43])[CH2:39][C@H:19]2[CH2:20][CH2:21][CH2:22][C:23]3[C:24](=[CH:25][C:26]4[CH:27]=[N:28][N:29]([C:32]5[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=5)[C:30]=4[CH:31]=3)[C@:18]2([CH2:40][NH2:41])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 0 °C

Procedure:
A suspension of LAH (38.0 mg, 1.00 mmol) in ether (1 mL) was stirred under nitrogen and cooled to 0° C. A solution of (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rx=Benzyl) (89 mg, 0.167 mmol) in THF (3 mL) was added maintaining reaction temperature under 5° C. and the mixture was allowed to stir at rt for about 54 h. The reaction was diluted with THF (2 mL) and quenched by addition of water (40 μL), then 2N NaOH (40 μL) and then water (80 μL). The reaction was stirred overnight at rt. The mixture was dried with Na2SO4 and filtered through Celite®, rinsing with THF (5 mL) and EtOAc (10 mL). The combined organics were concentrated under reduced pressure to yield crude ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methanamine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rx=Benzyl). LC/MS, method 3, Rt=2.41 min, MS m/z 538 (M+H)+. The residue was used in step #3 without further purification.
Reaction SMILES: C1COCC1.[CH3:6][C:7](=[O:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1>>[OH:27][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C:7](=[O:28])[CH3:6])[CH2:16]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
The reaction was carried out under a dry N2 atmosphere. Potassium ⟦trisamylborohydride⟧ trisiamylborohydride solution (KS-⟦Selectide⟧Selectride) in THF (6 cc, 5.83 mmol) was introduced into a three neck round bottom flask and cooled to 0° C. 5α-Pregnan-3,20-dione (1.58 g, 5 mmol) dissolved in 10 reducing agent. The resulting mixture was stirred vigorously for 2 hours at 0° C. and then allowed to equilibrate to room temperature for 1 hour. The reaction was quenched with 3 ml of water and 7 ml of ethanol. The organoborane was oxidized with 5 ml of 6 M NaOH and 7 ml of 30% H2O2. The reaction mixture was saturated with anhydrous potassium carbonate, and the organic layer was separated. The aqueous phase was neutralized with 0.1 N HCl and extracted with 20 ml of chloroform twice. The combined organic layers were dried over anhydrous MgSO4 and the solvent removed by rotary evaporation. Acetone was added to effect crystallization to produce a yield of 33%. The product has been identified by co-migration with authentic samples using silica based TLC and capillary GC. Melting point is 174°-175° C. Elemental analysis: Calc. C=79.19, H=10.76. Obs. C=78.86, H=10.70, NMR: 200 MHz ppm delta; 0.59 (s)(CH3), 0.77 (s)(CH3). 0.9-2.0 (m) (CH2), 2.1 (s)(CH3--C=O), 2.5 (t) (17-H), 4.02 (t) (3-H equatorial). The preparation method is a modification of the method shown in Gyermek et al., "Steroids CCCX. Structure-Activity Relationship of Some Steroidal Hypnotic Agents," J. Med. Chem., 11:117-125 (1968).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(F)c3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccc(F)c4)n3n2)cc1
Yield: 20.4 %

Procedure:
Applying the Cyclization Procedure 1, using 3-fluoro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 67) (130 mg, 0.35 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-(3-fluorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (25 mg) as a yellow solid. MS m/z 350 (M+1).
Reaction SMILES: [BH4-].[Li+].C(OC(=O)[C:7]([CH:9]1[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH3:15])=[O:8])C.Cl.C(N(CC)CC)C>C1COCC1>[O:14]1[CH:10]2[O:11][CH2:12][CH2:13][CH:9]2[CH:7]([OH:8])[CH2:15]1
Reactant: CCOC(=O)C(=O)C1CCOC1OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OC1COC2OCCC12
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
2 M Lithium borohydride solutions (24.7 ml) was added to the flask under nitrogen atmosphere. Ethyl-2-(2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (5 g) was dissolved in THF (25 ml) and slowly added at 65-70° C. Reaction mass was then maintained at 65-70° C. for 10 hrs. Reaction mass was cooled to −10° C. and slowly added concentrated hydrochloric acid (16 ml) and stirred for 2 hrs at −5 to 0° C. Triethyl amine (14.6 ml) was added to the reaction mass. Reaction mass was concentrated under vacuum. Ethyl acetate (20 ml) was added and again concentrated to residue. Ethyl acetate (50 ml) was added to it and filtered the un-dissolved salts. Filtrate was concentrated to get residue of Hexahydrofuro[2,3-b]furan-3-ol (yield 1.5 g).
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:26])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[NH:14][CH:15]=2)[O:5]1.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][N:14]1[CH:15]=[C:11]([B:6]2[O:5][C:4]([CH3:26])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)[CH:12]=[C:13]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: CC1(C)OB(c2c[nH]c(C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl iodide (0.27 mL, 4.3 mmol) was added to a mixture of benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (0.7 g, 2 mmol) and cesium carbonate (1.4 g, 4.3 mmol) in DMF (5.0 mL) and then the reaction was stirred at r.t. for 1 h. LCMS showed the reaction was complete. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-10%) to afford the desired product. LCMS (M+H)+: m/z=342.2.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl.C(OCC)C>[Cl:26][CH2:27][C:28]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)CC(OC(=O)CCl)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A mixture of 45.2 g (0.177 mol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 17.9 g (0.177 mol) of triethylamine, and 150 ml of dichloromethane is added over a 1 hour interval at 5° C. to a solution of 20.0 g (0.177 mol) of chloroacetyl chloride in 100 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 1 hour and then diluted with diethyl ether (500 ml). Solids are removed by filtration, and the filtrate is washed with 1N hydrochloric acid (2×100 ml), saturated sodium bicarbonate solution (200 ml), and saturated sodium chloride solution (200 ml), then dried over magnesium sulfate and concentrated to obtain an oil. Purification by flash chromatography on silica gel (5:1 heptane: ethyl acetate) affords 22.6 g (39% yield) of the title compound, a white solid, mp 62°-4° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20]C)=O)=[C:4](C(OC)=O)[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C[O-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:3]2[CH2:16][CH2:17][C:18](=[O:20])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: COC(=O)CCc1c(F)cc2nn(C)cc2c1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc2c3c(c(F)cc2n1)CCC3=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of methyl 6-fluoro-5-(3-methoxy-3-oxopropyl)-2-methyl-2H-indazole-4-carboxylate (407 mg, 1.38 mmol) in tetrahydrofuran (14 mL) was added a solution of sodium methoxide (28%, 533 mg, 2.76 mmol) in methanol, and the mixture was stirred at 60° C. for 1 hr. The reaction solution was concentrated to dryness, 10% aqueous sulfuric acid solution (14 mL) was added, and the mixture was heated under reflux for 3 hr. The reaction solution was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (269 mg, yield 95%).
Reaction SMILES: O.[CH:2]([O-:4])=[O:3].[NH4+].Cl[C:7]1[S:8][C:9](Cl)=[C:10]2[C:14](=C=O)[N:13](OC(C)(C)C)[CH2:12][C:11]=12>CO.[Pd]>[CH3:9][C:10]([CH3:14])([O:3][C:2]([N:13]1[CH2:12][C:11]2=[CH:7][S:8][CH:9]=[C:10]2[CH2:14]1)=[O:4])[CH3:11]
Reactant: CC(C)(C)ON1Cc2c(Cl)sc(Cl)c2C1=C=O
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cscc2C1
Yield: 134.3 %

Procedure:
17.6 g of 10% palladium-on-charcoal containing 50% of water and then 41.6 g (600 mmol) of ammonium formate are added to a solution of 8.82 g (30 mmol) of 1,3-dichloro-5(1,1-dimethylethoxy)-carbonyl-5,6-dihydro-4H -thieno[3,4-c]pyrrole in 75 ml of methanol. The mixture is heated at reflux for 24 hours and it is then cooled, filtered through a Celite column, rinsed with twice 50 ml of dichloromethane and evaporated to dryness. The residue is taken up in 100 ml of dichloromethane, filtered and evaporated to dryness. There are obtained 4.54 g of an oily product which crystallizes slowly. Yield 68%. Melting point: 36°-38° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(Cl)cnn1C
Yield: 49.2 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3-Chlorophenyl isocyanate (17 μL, 0.14 mmol) in a similar manner to Example 1.53, providing 25 mg (46%) of Compound 91: LCMS m/z (%)=391 (M+H35Cl, 100), 393 (M+H37Cl, 70). 1H NMR (400 MHz, acetone-d6) δ: 8.51 (s, 1H), 8.41 (s, 1H), 7.84 (t, 1H), 7.71 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.49 (s, 1H), 7.49 (d, J=2 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.29 (t, 1H), 7.16 (d, J=8 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [S:1]([C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:24]=1[O:39][CH2:40][O:41][CH2:42][CH3:43])C1C=C(C2C=CC(C(F)(F)F)=CC=2)C=CC=1OCOCC.C(S([O-])=O)O.[Na+].C(=O)([O-])[O-].[K+].[K+].[F:56][C:57]([F:61])([F:60])[CH2:58]I>CN(C)C=O.O>[F:56][C:57]([F:61])([F:60])[CH2:58][S:1][C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:24]=1[O:39][CH2:40][O:41][CH2:42][CH3:43]
Reactant: CCOCOc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Sc1cc(-c2ccc(C(F)(F)F)cc2)ccc1OCOCC
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOc1ccc(-c2ccc(C(F)(F)F)cc2)cc1SCC(F)(F)F
Yield: 151.1 %

Procedure:
3.3 g (5.0 mmol) of 1,1′-thiodi-[2-ethoxymethoxy-5-(4-trifluoromethylphenyl)benzene], 3.0 g (19.5 mmol) of Rongalite, 3.0 g (21.7 mmol) of potassium carbonate and 3.2 g (17.6 mmol) of 2,2,2-trifluoroethyl iodide were stirred in 50 ml of N,N-dimethylformamide at room temperature for 3 hours. The resulting reaction mixture was poured into 300 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 3.1 g of (2-ethoxymethoxy-5-(4-trifluoromethylphenyl)phenyl] 2,2,2-trifluoroethyl sulfide (yield 75.6%) as a pale yellow viscous liquid (nD20 1.5213).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:55])[CH2:24][CH2:25][CH2:26][N:27]([C:29]4[CH:30]=[CH:31][C:32]([C:35]5[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43]CC6C=CC(OC)=CC=6)=[C:37]([O:53][CH3:54])[CH:36]=5)=[N:33][CH:34]=4)[CH3:28])=[CH:19][N:18]=3)=[CH:11][C:10]=2[O:56][CH3:57])=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:55])[CH2:24][CH2:25][CH2:26][N:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[C:39]([O:41][CH3:42])[C:38]([OH:43])=[C:37]([O:53][CH3:54])[CH:36]=4)=[N:33][CH:34]=3)[CH3:28])=[CH:19][N:18]=2)=[CH:11][C:10]=1[O:56][CH3:57]
Reactant: COc1ccc(COc2c(OC)cc(-c3ccc(N(C)CCCN(C)c4ccc(-c5cc(OC)c(OCc6ccc(OC)cc6)c(OC)c5)nc4)cn3)cc2OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc(N(C)CCCN(C)c3ccc(-c4cc(OC)c(O)c(OC)c4)nc3)cn2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of N,N′-bis[2-[4-(4-methoxybenzyloxy)-3,5-dimethoxyphenyl]-5-pyridyl]-N,N′-dimethyl-1,3-propanediamine (72.0 mg, 0.089 mmol) in methylene chloride (1.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. A solution of the residue in chloroform was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield N,N′-bis[2-(4-hydroxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethyl-1,3-propanediamine as a pale yellow oil (43.0 mg, yield: 86%).