Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[O:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18].[OH-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[OH:1][CH2:2][CH:3]1[CH:8]2[O:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCC1C2CCC(O2)C1Cc1cc(F)ccc1O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCC1C2CCC(O2)C1Cc1cc(F)ccc1OCc1ccccc1
Yield: 94.5 %

Procedure:
To a solution of [1S-(1α, 2α, 3α, 4α)]-2-[[3-[hydroxymethyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-4-fluoro-phenol (0.71 g, 2.8 mmol) in ethanol (30 mL) was added potassium hydroxide (0.173 g, 3.08 mmol) and the resulting mixture was refluxed until the potassium hydroxide dissolved. Then benzyl bromide (0.332 mL, 2.8 mmol) was added and the reaction was left to reflux for 16 h. After this time, the reaction was stopped and the solvent was evaporated under vacuum. The crude product was partitioned between ethyl acetate (30 mL) and 2M HCl (15 mL). The organic phase was separated; washed with a sat. solution of sodium bicarbonate (15 mL), brine (15 mL), dried (MgSO4), filtered and the solvent was evaporated “under vacuum” to give the crude product as an oil. The crude product was purified by chromatography column on a 20G SPE cartridge using ethyl acetate/hexane 1:2 as eluent to isolate 0.906 g (94%) of titled product as an oil. 1H-NMR (CDCl3, 300 MHz) δ 7.37(m, 5H, ArH), 6.86 (m, 3H, ArH), 5.08 (s, 2H, —OCH2Ph), 4.56 (d, 1H, J=4.9 Hz, —CH—O—), 4.27 (d, 1H, J=4.9 Hz, —CH—O—), 3.74 (m, 2H, —CH2OH), 2.86 (dd, 1H, J=4.4, 13.9 Hz, —CH—), 2.53 (dd, 1H, J=11.3, 13.7 Hz, —CH—), 2.29 (m, 1H, —CH2—), 2.08 (m, 1H, —CH2—), 1.80-1-32 (m, 4H, —CH2—CH2—)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=2)=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:26][C:24]([F:25])([F:27])[C:14]1[CH:13]=[C:12]([S:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)[CH:17]=[CH:16][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzoic acid methyl ester (83 mg, 0.2062 mmol, 1 eq.) in anhydrous toluene (5 mL) cooled to −78° C. is added DIBAL-H (1 M in toluene, 0.41 mL, 0.41 mmol, 2 eq). The mixture is stirred at −78° C. for 30 min. The reaction is quenched by the addition of saturated aqueous NH4Cl after which point the reaction mixture is allowed to warm to room temperature. The reaction is diluted with EtOAc and washed with 1 N HCl (aq), H2O, and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:1 hexanes/EtOAc) to give [4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-phenyl]-methanol. [MS: (ES+) 397.1 (M+23)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC>CN(C=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>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([C:23](=[O:25])[CH3:24])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Temperature: 80 °C
Yield: 101.7 %

Procedure:
In a screw top flask 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (1.6 g, 6.1 mmol), tributyl-(1-ethoxy-vinyl)-stannane (1.8 g, 4.8 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) (212 mg, 0.30 mmol) were combined in DMF (10 mL). Under nitrogen the flask was sealed and heated to 80° C. for 12 hours. The reaction mixture was cooled to rt, concentrated, and purified by flash column chromatography using ethyl acetate-hexanes (0%-20%) to provide the desired product as a clear oil (1.3 g, 73%). MS (ESI): mass calcd. for C15H13F3N2O, 294.0; m/z found 295.1 [M+H]+. The resulting clear oil was diluted with THF (60 mL) and 2N HCl (10 mL) and stirred. After 12 h, the resulting solution was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried with Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography using ethyl acetate-hexanes (0%-20%) to provide the desired product as a clear oil (1.1 g, 93%). MS (ESI): mass calcd. for C13H9F3N2O, 266.0; m/z found 267.1 [M+H]+. 1H NMR (CDCl3) δ 9.45 (d, J=1.3 Hz, 1H), 8.37 (d, J=1.3 Hz, 1H), 8.31 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@@H:6]([CH2:14][OH:15])[CH2:5]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:8][C@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@@H:6]([CH2:14][O:15][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCN1C[C@H](CO)[C@@H](c2ccsc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccsc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.3 %

Procedure:
A solution of 1.06 g (4.75 mmol) of 1-(prop-2-enyl)(3-(R)-(hydroxymethyl))-4-(S)-(3-thienyl)pyrrolidine (from EXAMPLE 87, Step A) in 12.0 mL of CH2Cl2 at 0° C. was treated with 0.99 mL (5.7 mmol) of DIEA and 855 mg (5.6 mmol) of t-butyldimethyl silyl chloride. After warming to rt and stirring for 20 h, the solution was partitioned between 100 mL of ether and 100 mL of H2O. After separating the phases, the aqueous layer was extracted with 100 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 3:1 v/v hexanes/EtOAc to yield 1.24 g (77%) of the title compound: RF: 0.54 (3:2 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.0 (s, 6H), 0.86 (s, 9H), 2.35 (m, 1H), 2.52-2.71 (m, 3H), 2.97-3.20 (m, 4H), 3.54-3.66 (m, 2H), 5.06-5.21 (m, 2H), 5.89 (m, 1H). 6.98-7.02 (m, 2H), 7.22 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3C(=C[CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][CH2:12][CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[Br:22][C:23]1(Br)NC(=O)N[C:24]1=[O:29]>>[Br:22][C@:23]12[CH:24]([OH:29])[CH2:21][C@@:20]3([CH3:19])[C@@H:6]([CH2:5][CH2:4][C@@H:3]3[CH2:2][CH3:1])[C@@H:7]1[CH2:8][CH2:9][C:10]1[C@:15]2([CH3:16])[CH:14]=[CH:13][CH2:12][CH:11]=1
Reactant: O=C1NC(=O)C(Br)(Br)N1
Reactant: CC[C@H]1CC[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)C3=CC[C@]12C
Product: CC[C@H]1CC[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)[C@@]3(Br)C(O)C[C@]12C

Procedure:
The pregna-1,4,9(11)-trienes represented by formula (A) above are converted to various intermediates by means known in the art. For example they are treated with chlorine according to the process of U.S. Pat. No. 3,009,933 to give the corresponding 9α,11β-dichloropregna-1,4-diene ##STR15## The 9α-fluoro-11β-hydroxy compound is prepared by reacting the appropriate pregna-1,4,9(11) triene with dibromohydantoin to form the 9α-bromo-11-hydroxypregna-1,4-diene which in turn is reacted with sodium hydroxide to give the corresponding 9β,11β-epoxide. This epoxide is then treated with a hydrogen fluoride/urea complex according to the process set forth in U.S. Pat. No. 3,211,758 to Tarkoey to give the 9α-fluoro-11β-hydroxy compound. The 9α-chloro-11β-hydroxy compound is prepared by reacting the 9β,11β-epoxide with hydrogen chloride in methylene chloride or by reacting the Δ9,(11) steroid with dichlorohydrantoin. An 11β-hydroxy (9-unsubstituted) steroid is readily prepared by methods well known in the art such as employing Cunninghamella blakesleena, Cunninghamella bainieri, Curvularia lunata or other suitable micro-organisms in a suitable medium which selectively affords the desired 11-hydroxy steroid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2(O)[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH:11]=[CH:12][CH:13]=1>CO.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]2[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(OCCCCCCl)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2c2cccc(OCCCCCCl)c2)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
4-[3-(5-Chloropentyloxy)phenyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (307 mg, 0.56 mmol) was dissolved in methanol (15 ml), and 10% Pd/C (102 mg) was slowly added dropwise thereto. Then the reaction mixture was stirred under hydrogen atmosphere for 2 hours and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 283 mg (yield: 95%, 3RS,4RS/3RS,4SR=1:1) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3].[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9]>>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[Cl:1][CH2:9][CH2:8][N:11]=[C:12]=[O:13].[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9]
Reactant: CC(Cl)NC(=O)Cl
Agent: CC(C)N=C=O
Product: C=CN=C=O
Product: O=C=NCCCl
Temperature: 70 °C
Yield: 43 %
Yield: 2 %

Procedure:
57 parts of 1-chloroethylcarbamic acid chloride are introduced into 700 parts by volume of isopropyl isocyanate at 22° C., the mixture is heated to 70° C. in the course of 1.5 hours whilst passing a slight stream of nitrogen through it, and the reaction mixture is condensed in a cold trap at -70° C. 12 parts (43% of theory) of vinyl isocyanate of boiling point 38.5° C./1013 mbar, 0.85 part (2% of theory) of chloroethyl isocyanate of boiling point 92° C./1013 mbar and 218 parts of isopropyl isocyanate are obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:44]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:45])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)C1CCCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (see example 8) as described in general procedure D using cyclohexanecarbonyl chloride. The final product was obtained in 74% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccnc(F)c2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of 1,1-dimethylethyl(4RS,5SR)-5-(2-fluoropyridin-4-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (1.30 g, 2.66 mmol) in methanol (7 ml) was added a solution (6.39 ml, 3.19 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.08 g, 88%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].C(N(CC)CC)C.O>CN(C)C(=O)C>[C:2]1([C:1]2[O:8][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Yield: 81.8 %

Procedure:
In a 500 ml three-necked flask provided with magnetic stirrer, reflux condenser, drying tube and dropping funnel, 2.81 g (20 mmol) of benzoyl chloride were dissolved in 50 ml of N,N-dimethylacetamide and 2.74 g (20 mmol) of 2-aminobenzoic acid as powder were added thereto while stirring. A mixture of 2.02 g (20 mmol) of triethylamine and 5 ml of N,N-dimethylacetamide were subsequently slowly added dropwise at room temperature. After stirring at room temperature for 1 hour, 200 ml of water were added and the precipitate formed was filtered off with suction, washed with water and dried at 80° C. under reduced pressure. The product was then heated in 50 ml of acetic anhydride under reflux for 2 hours. After cooling, the precipitate formed was filtered off with suction and washed with acetic acid and then with water. Recrystallization from n-hexane gave 3.65 g of product.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH:9]=[C:8]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][C:7]2=[N:6]1)(=[O:4])=[O:3].[C:20]1([S:26]([OH:29])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OC(=O)C)(C)C>[C:20]1([S:26]([O-:29])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:1][S:2]([N:5]1[CH:9]=[C:8]2[CH2:10][NH2+:11][CH2:12][C:7]2=[N:6]1)(=[O:3])=[O:4]
Reactant: O=S(=O)(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2cn(S(C)(=O)=O)nc2C1
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)n1cc2c(n1)C[NH2+]C2
Product: O=S(=O)([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (32.1 kg, 111 mol) in iso-propylacetate (289 kg) was added benzenesulfonic acid (35.35 kg, 223 mol). The reaction was stirred for 3 days at room temperature and then cooled to 0-10° C. and stirred an additional 1 h. The resulting slurry was filtered and the cake washed with iso-propylacetate. The solids were dried overnight under vacuum at room temperature to give 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:2]=1.BrC1C=NC=CC=1.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:40]1[CH2:43][CH:42]([NH:44][C:45](=[O:62])[CH2:46][NH:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[C:55]([C:58]([F:61])([F:60])[F:59])[CH:56]=3)[N:51]=[CH:50][N:49]=2)[CH2:41]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][CH:10]([N:40]3[CH2:41][CH:42]([NH:44][C:45](=[O:62])[CH2:46][NH:47][C:48]4[C:57]5[C:52](=[CH:53][CH:54]=[C:55]([C:58]([F:59])([F:61])[F:60])[CH:56]=5)[N:51]=[CH:50][N:49]=4)[CH2:43]3)[CH2:9][CH2:8]2)[CH:2]=1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2cccnc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: [Na+]
Solvent: Brc1cccnc1
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3cccnc3)CC2)C1

Procedure:
Reaction of 4-(pyridin-3-yl)cyclohexanone (prepared by the reaction of 3-bromopyridine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (MeOD) δ: 8.62 (s, 1 H), 8.56 (s, 1 H), 8.43 (d, J=2.0 Hz, 1 H), 8.33 (dd, J=5.1, 1.5 Hz, 1 H), 8.04 (dd, J=8.8, 1.8 Hz, 1 H), 7.88 (d, J=8.8 Hz, 1 H), 7.77 (dt, J=7.8, 1.8 Hz, 1 H), 7.35 (dd, J=7.7, 5.2 Hz, 1 H), 4.51 (quin, J=7.1 Hz, 1 H), 4.28 (s, 2 H), 3.65-3.73 (m, 2 H), 2.95 (t, J=7.6 Hz, 2 H), 2.56-2.69 (m, 1 H), 2.43 (d, J=2.8 Hz, 1 H), 1.68-1.92 (m, 4 H), 1.49-1.62 (m, 4 H); ESI-MS (m/z): Calcd. For C25H27F3N6O: 484.22. found: 485 (M+H).
Reaction SMILES: CNC.C=O.CC1NC=NC=1C[CH:13]1[C:25](=[O:26])[N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>C(O)(=O)C>[CH:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[C:16]1[CH:15]=[CH:14][CH2:13][C:25](=[O:26])[N:17]12
Reactant: Cc1[nH]cnc1CC1CCc2cc3ccccc3n2C1=O
Agent: C=O
Agent: CNC
Solvent: CC(=O)O
Product: O=C1CC=Cc2cc3ccccc3n21
Reaction time: 24 h
Yield: 87.5 %

Procedure:
To a mixture of aqueous 50% dimethylamine solution (0.20 ml), aqueous 35% formaldehyde solution (0.20 ml), and acetic acid (4 ml) at 15° C. was added 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (418 mg). The mixture was heated at 60°]C. for 24 hours. After evaporation of the solvent, the residue was dissolved in water, made basic with aqueous 3N sodium hydroxide solution, and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The oil was purified by silica gel column chromatography (20% methanol-chloroform) to give 8,9-dihydro-10-[(dimethylamino)methyl]-7-(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (240 mg).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH2:14]([C:12]1[S:13][C:9]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:4][CH2:3]2)=[CH:10][N:11]=1)[CH3:15]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CCc1ncc(C2(O)CCC(=O)CC2)s1
Product: CCc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-ethyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cnc1N
Yield: 95.8 %

Procedure:
A suspension of 5-fluoro-3-nitro-2-pyridinamine (561 mg, 3.573 mmol) in ethanol (100 ml) was treated with added 10% Pd/C (100 mg) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 5 h. The reaction mixture was then filtered through a thin pad of Celite, washing through with EtOH (500 ml). The filtrate was evaporated to give the desired product as a grey solid (435 mg, 96%).
Reaction SMILES: OCCNC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[CH2:38]([O:45][C:46]1[C:47]([C:66]([NH:68][CH2:69][CH2:70][O:71][Si](C(C)(C)C)(C)C)=[O:67])=[N:48][C:49]([CH2:53][C:54]2([C:59]3[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=3)[CH2:58][CH2:57][CH2:56][CH2:55]2)=[N:50][C:51]=1[OH:52])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]1[C:47]([C:66]([NH:68][CH2:69][CH2:70][OH:71])=[O:67])=[N:48][C:49]([CH2:53][C:54]2([C:59]3[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=3)[CH2:55][CH2:56][CH2:57][CH2:58]2)=[N:50][C:51]=1[OH:52])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(NCCO)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(NCCO)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-amide (347) from 5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxamide (514).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][N:17](CC2C=CC=CC=2)[CH2:18]3)[CH:7]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][NH:17][CH2:18]3)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)c3c2CN(Cc2ccccc2)C3)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)c3c2CNC3)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of [3-(2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (246 mg, 0.59 mmol, 1 eq.) in ethanol (40 mL), palladium on activated carbon (20 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo to give the desired product. The product was used without further purification.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[C:11]([F:20])[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:19])[CH2:16][O:17][CH2:18]2)=[C:11]([F:20])[CH:10]=1
Reactant: OC1(c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2F)COC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)COC2)c(F)c1
Reaction time: 16 h
Yield: 83 %

Procedure:
To a stirred solution of 3-(4-(dibenzylamino)-2-fluorophenyl)oxetan-3-ol (2.15 g, 5.92 mmol, 1.0 eq) in THF (125 mL) was added 10% Pd/C (0.230 g) under argon and stirred under hydrogen balloon pressure for 16 h. The mixture was passed through celite, and the filtrate concentrated under vacuum. The resulting crude product was purified by CC using EtOAc/PE (7:3) to get 3-(4-amino-2-fluorophenyl)oxetan-3-ol (0.9 g, 73%; TLC system: EtOAc 100%, 0.5).