Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=O)[N:5]=[C:4]2[C:18]([C:21]3[S:25][C:24]([CH3:26])=[N:23][CH:22]=3)=[N:19][O:20][C:3]=12.[NH:27]1[C:34](=[O:35])[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[O:29]>C(O)(C)C>[Cl:1][C:2]1[C:3]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH3:26])=[N:23][CH:22]=3)[C:4]=2[N:5]=[C:6]2[C:7]=1[N:8]1[CH2:9][C@@H:10]([CH3:15])[O:11][C@@H:12]([CH3:14])[C@@H:13]1[C:33]1([C:31](=[O:32])[NH:30][C:28](=[O:29])[NH:27][C:34]1=[O:35])[CH2:16]2
Reactant: Cc1ncc(-c2noc3c(Cl)c(N4C[C@@H](C)O[C@@H](C)C4)c(C=O)nc23)s1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: Cc1ncc(-c2noc3c(Cl)c4c(nc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)s1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
To isopropanol (20 ml) was added to 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-(2-methylthiazol-5-yl)isoxazolo[4,5-b]pyridine-5-carbaldehyde (Intermediate 414, 0.26 g, 0.66 mmol) and barbituric acid (0.085 g, 0.66 mmol), and the mixture was heated to 80° C. for about 2 days. The mixture was concentrated, and crystallization of the crude mixture from methanol gave 45 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>>[CH2:18]([N:13]1[C:12]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: OB(O)c1cccs1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1cccs1)CCNCC2
Yield: 114.1 %

Procedure:
The title compound (101 mg) was prepared as in Example 177, Steps C and D, using 148 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 306 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C13H17N3S, 247.11. found, m/z 248.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.62-7.57 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.05 (m, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.33-3.27 (m, 2H), 3.24-3.18 (m, 2H), 3.07-3.01 (m, 2H), 2.80-2.73 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C>CN(C=O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:30]([CH3:32])[CH3:29])[CH2:10][C@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 60 °C

Procedure:
To (R)-1-Boc-2-methylpiperazine (200.0 mg, 0.999 mmol) and sodium triacetoxyborohydride (444.5 mg, 2.097 mmol) in DMF (5 mL) was added acetone (116 mg, 0.147 mL, 1.997 mmol) and acetic acid (90.0 mg, 86 μL, 1.498 mmol). The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was diluted with water and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered, concentrated, and used without further purification. LCMS-ESI+: calc'd for C13H27N2O2 (M+H+): 243.2; Found: 243.1 (M+H+).
Reaction SMILES: [Li].[H-].[C:3]([S@:7]([NH:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]([CH:22]=1)[C:17](OCC)=[O:18])[CH3:11])=[O:8])([CH3:6])([CH3:5])[CH3:4].[F-].[K+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:3]([S@:7]([NH:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[C:16]([CH2:17][OH:18])[CH:22]=1)[CH3:11])=[O:8])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1cc([C@@H](C)N[S@](=O)C(C)(C)C)ccc1NS(C)(=O)=O
Agent: O=S(=O)([O-])[O-]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(NS(C)(=O)=O)c(CO)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of lithium alminium hydride (1.6 g, 43 mmol) in tetrahydrofuran (THF) (50 ml) was added a solution of ethyl 5-((1R)-1-{[(R)-tert-butylsulfinyl]amino}ethyl)-2-[(methylsulfonyl)amino]benzoate (4.2 g, 11 mmol) in tetrahydrofuran (THF) (100 ml) at 0° C. After being stirred for 3 hours at 0° C., potassium fluoride and sodium sulfate decahydrate were added. After being stirred for 5 hours, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give 3.6 (97% yield) of the title compound as slightly yellow oil. MS (ESI) m/z 391 [M+H]+, 389 [M−H]−.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C@@:14]2([N:22]3[C:32]4[N:31]=[C:29]([NH2:30])[NH:28][C:26](=[O:27])[C:25]=4[N:24]=[CH:23]3)[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:33][O:34][C:35]1[CH:56]=[CH:55][C:38]([C:39](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:37][CH:36]=1>N1C=CC=CC=1>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C@@:14]2([N:22]3[C:32]4[N:31]=[C:29]([NH2:30])[NH:28][C:26](=[O:27])[C:25]=4[N:24]=[CH:23]3)[O:21][C@H:18]([CH2:19][O:20][C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:56][CH:55]=3)[C@@H:16]([OH:17])[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CC(=O)[C@]2(n3cnc4c(=O)[nH]c(N)nc43)C[C@H](O)[C@@H](CO)O2)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@](C(=O)Cc3cccc(OC)c3)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 45.6 %

Procedure:
N2 -(3-Methoxyphenylacetyl)-2'-deoxyguanosine (2b) (2.08 g, 5 mmoles) was dried by coevaporation with dry pyridine (2×30 ml), dissolved in 40 ml of dry pyridine and ice cooled. To this solution, 4,4'-dimethoxytrityl chloride (2.2 g, 6.5 mmoles) was added. The reaction mixture was stirred at 5° C. for 20 hours. After removing the pyridine under reduced pressure, the resulting residue was taken up in 150 ml of methylene chloride and washed successively with 2×100 ml of 5% NaHCO3 and 1×100 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated to near dryness. The product was purified on a silica gel column (2×40 cm) by gradient elution with 200 ml 0-6% methylene chloride-methanol. The desired fractions were collected, concentrated to about 30 ml and added dropwise to 200 ml cooled hexane (0° C.) to precipitate the product. The precipitated product was filtered, washed with hexane and air dried to yield 1.7 g (47%) of tritylated product (3b), as confirmed by spectroscopic and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][CH:28]([CH3:29])[CH3:30])#[N:24]
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Reactant: CC(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (0.6 g), 5-amino-2-isobutoxybenzonitrile (0.5 g), triethylamine (0.8 g) and diethyl cyanophosphate (0.7 g) were added to dimethylformamide (8 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.2 g), melting point: 179–180° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:23]4[CH:24]=[CH:25][S:21][CH:22]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: OB(O)c1ccsc1
Product: O=C1NC(=O)c2c1c(-c1ccsc1)cc1[nH]c3ccc(O)cc3c21
Yield: 74 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-thienylboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(3-thienyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (12) (I, Ar=3-thienyl) in a 74% yield; mp 247° C. (dec). 1H NMR δ [(CD3)2SO] 11.73 (br s, 1H), 11.05 (br s, 1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.92 (dd, J=5.0, 2.7 Hz, 1H), 7.70 (s, 1H), 7.61 (dd, J=5.0, 2.7 Hz, 1H), 7.51 (dd, J=5.0, 0.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H). Found: C, 61.05; H, 2.96; N, 7.60. C18H10N2SO3,H2O requires C, 61.36; H, 3.43; N, 7.95.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:34]4[C:33](=[C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]5=[CH:36][CH:35]=4)[NH:43][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 544.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C@H:34]([CH2:35][O:36]CC2C=CC=CC=2)[C@@H:25]([O:26]CC2C=CC=CC=2)[C@H:16]([O:17]CC2C=CC=CC=2)[C@@H:7]([O:8]CC2C=CC=CC=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CO.O.[Pd]>[CH3:4][CH2:3][CH2:2][CH2:1][N:5]1[C@H:34]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:16]([OH:17])[C@@H:7]([OH:8])[CH2:6]1
Reactant: CCCCN1C[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CO
Solvent: O
Product: CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 4 h

Procedure:
A solution obtained by mixing N-butyl 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol of formula (III), obtained as in Example 2 (105.1 g, 0.17 mol) in methanol (500 ml) in the presence of 32% HCl (43.5 g). is treated with 16% Pd/C (10.2 g). The mixture is maintained under vigorous stirring under hydrogen atmosphere at 4 bars for about 4 hours, and then filtered through a perlite panel, and the solution obtained is concentrated at low pressure. The solid residue thus obtained is dissolved in water (100 ml), and the resulting acid solution is passed through a column on an ion-exchange resin activated in basic form (Amberlite IRA 900Cl). The fractions that tested positive to the ninhydrin assay were combined and concentrated at low pressure, obtaining 50 g of miglustat as an oily residue, having a chemical purity exceeding 98%, calculated by HPLC.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]O.N1C=CC=CC=1>CCOCC>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10][Cl:3]
Reactant: COc1cc(CO)cc(OC)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cc(CCl)cc(OC)c1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Over a period of 20 minutes a solution of 150 g (1.26 moles) of thionyl chloride in 0.65 l of ether was added to 100 g (0.59 moles) of 3,5-dimethoxybenzyl alcohol and 6.6 ml of pyridine in 1.35 l of ether. After stirring for 3 hr the solution containing the product was separated from the residual dark oil, concentrated, and the crude product was redissolved in 1 l of ether, washed with water (3×250 ml), dried (brine, magnesium sulfate), filtered, and reconcentrated to give a dark oil which was vacuum distilled: b.p. 115°-118° C. at 0.4 mm Hg. Upon standing, fractions containing the desired compound solidified to give 95.3 g (86%) of white solid, m.p. 43°-45° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[C:16](OC=O)(=[O:18])C>CN(C)C=O>[CH:16]([NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5])=[O:18]
Reactant: CC(=O)OC=O
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: O=CNc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
To a solution of 4.7 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide in 30 ml of dimethylformamide, under nitrogen, was added 4.7 g of freshly prepared formic acetic anhydride. The precipitate which formed within a few minutes was separated by filtration and washed with ether to give 2-(formylamino)-N-(1H-tetrazol-5-yl)benzamide melting at about 247°-248° C. This compound has the following structural formula: ##STR2##
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:42][CH3:43])[C:34]=2[C:38]([F:41])([F:40])[F:39])[C:29]=1[CH3:44]>C(Cl)(Cl)(Cl)Cl>[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:42][CH3:43])[C:34]=2[C:38]([F:40])([F:41])[F:39])[C:29]=1[CH2:44][Br:1]
Reactant: COc1ccc2c(C)c(Br)ccc2c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(CBr)c(Br)ccc2c1C(F)(F)F
Yield: 100 %

Procedure:
N-Bromosuccinimide (21.07 g, 1.5 eq) and benzoyl peroxide (84 mg, 0.0044 eq) were added to a stirred solution of 2-bromo-6-methoxy-1-methyl-5-trifluoromethylnaphthalene (25.19 g, 78.9 mmol, prepared by the process of Example 14, Step (1) in carbon tetrachloride (300 mL) at room temperature under a dry nitrogen atmosphere. The reaction was heated to reflux for 6 hours, then cooled to ~50° C. The warm reaction mixture was filtered. The solid washed with warm carbon tetrachloride (2×30 mL). The carbon tetrachloride was removed from the filtrate to provide the light yellow solid (32.4 g, 100%), m.p. 141.5°-143° C.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[O:5]1[CH2:9][CH2:8][CH2:7][S:6]1(=[O:11])=[O:10]>C1COCC1>[CH2:1]([NH:4][CH2:9][CH2:8][CH2:7][S:6]([OH:11])(=[O:10])=[O:5])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: C#CCNCCCS(=O)(=O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4 g (71.2 mmol) prop-2-yn-1-amine were dissolved in 75 ml THF and cooled to 0° C. To this mixture 8.87 g (71.2 mmol) 1,2-oxathiolane 2,2-dioxide dissolved in 25 ml THF were added drop wise at 0° to 5° C. After addition the reaction mixture was heated to room temperature and stirred for 12 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][F:23]>C(#N)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:21][CH2:22][F:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=N)SCCF)c1
Yield: 9 %

Procedure:
To a mixture of the compound (500 mg) obtained in Example 24 and acetonitrile (20 ml) was added 1-bromo-2-fluoroethane (0.26 ml) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was distilled under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and the organic layer was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 50 mg of the titled compound (yield, 9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].N>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: N
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
A solution of 3,5-difluorobenzonitrile (4 g, 28.8 mmole) in methanol saturated with ammonia (100 ml) was added to a slurry of methanol washed Raney nickel. The mixture was shaken under 50 psi hydrogen for 1.5 hours, filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate and extracted with 3N HCl. The acidic solution was basified with 50% sodium hydroxide and was extracted into ethyl acetate. The organic extract was dried (Na2SO4) and concentrated to give 3.0 g (74%) of title compound as a yellow oil which was stored under nitrogen.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncccc1-c1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ncccc1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:22][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[OH:23][C@H]1CC[C@@]2(C)[C@@]3(O[C@@H]3C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1.CC(O)C>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[OH:22][C@:4]12[CH2:3][C:2](=[O:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 75 %

Procedure:
To a solution of a 1/1 mixture of 3β-hydroxy-5α,6α-epoxyandrostan-17-one and 3β-hydroxy-5β,6β-epoxyandrostane-17-one (2.10 g, 6.90 mmol) in acetone (38 mL), Jones reagent (8.35 mL) was added dropwise, maintaining the temperature below 40° C. 5 min after completion of the addition, i-PrOH (10 mL) was added and, after further 10 min, the suspension was filtered and the filtrate evaporated to dryness. The residue was treated with H2O (300 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (100 mL), 5% aqueous NaHCO3 solution (100 mL), H2O (100 mL), dried over Na2SO4 and evaporated to dryness to give 5α-hydroxyandrostane-3,6,17-trione as a white solid (1.65 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.00 (s, 1H), 2.85 (m, 2H), 2.45-1.25 (m, 17H), 1.06 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [Li+].[Br-].[BH4-].[Na+].[O:5]=[C:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:15][C:16](OCC)=[O:17])[CH:12]=2)[NH:7]1.B(OC)(OC)OC.[Na+].[Cl-]>C1COCC1>[OH:17][CH2:16][CH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:5])[CH2:14]2
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(=O)N2
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C1Cc2cc(CCO)ccc2N1

Procedure:
LiBr (1.03 g) is added to a solution of NaBH4 (0.45 g) in THF (15 ml). The reaction mixture is heated at reflux for 7 hours, and the compound obtained in Step B (1.3 g) is added, followed by B(OMe)3 (0.067 ml). After refluxing for 18 hours, the mixture is concentrated under reduced pressure and the residue obtained is taken up in 20 ml of 3NH2SO4. The aqueous phase is saturated with NaCl and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness. The residue is purified on silica gel (SiO2, eluant: AcOEt) to yield the title product in the form of a beige solid. The compound obtained is used directly in the next reaction.
Reaction SMILES: CN(C1C=CC2C(C)=CCC(C)(C)C=2C=1)C1C=CC(C(O)=O)=CC=1.[CH2:25]([O:27][C:28](=[O:50])[C:29]1[CH:34]=[CH:33][C:32]([N:35](C)[C:36]2[CH:45]=[CH:44][C:43]3[C:42]([CH3:46])=[CH:41][CH2:40][C:39]([CH3:48])([CH3:47])[C:38]=3[CH:37]=2)=[CH:31][CH:30]=1)[CH3:26].[OH-].[K+]>C(O)C>[CH2:25]([O:27][C:28](=[O:50])[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:42]([CH3:46])=[CH:41][CH2:40][C:39]([CH3:48])([CH3:47])[C:38]=3[CH:37]=2)=[CH:33][CH:34]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(N(C)c2ccc3c(c2)C(C)(C)CC=C3C)cc1
Agent: CC1=CCC(C)(C)c2cc(N(C)c3ccc(C(=O)O)cc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3C)cc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
PNMR (300 MHz, CDCl3) δ 1.28 (s, 6 H), 1.38 (t, 3 H, J=7.1 Hz), 2.06 (s, 3 H), 2.19 (d, 2 H, J=4.3 Hz), 4.35 (q, 2 H J=7.1 Hz), 5.68 (t, 1 H, J=4.3 Hz), 6.04 (s 1 H, NH), 6.98 (overlapping d & dd, 3 H), 7.11 (d, 1 H, J=2.3 Hz), 7.21 (d, 1 H, J=8.2 Hz), 7.93 (d, 2 H, J=8.8 Hz). 4-Methyl-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid ethyl ester (Compound 66) General Procedure M To a solution of4-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester (Compound 65, 31 mg, 0.09 mmol) in a 10% acetic acid in acetonitrile solution (1.0 mL) and 1.0 mL of ether were added formaldehyde (0.10 mL, 3.60 mmol) and then sodium cyanoborohydride (14 mg, 0.22 mmol) and the reaction stirred at room temperature for 1 h. 1 M aqueous NaOH was added until pH=6 and the resulting mixture was extracted twice with ethyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the title compound as yellow oil. PNMR (300 MHz, CDCl3) δ 1.24 (s, 6 H), 1.37 (t, 3 H, J=7.1 Hz), 2.08 (s, 3 H), 2.23 (d, 2 H, J=4.4 Hz), 3.38 (s, 3 H), 4.34 (q, 2 H, J=7.1 Hz), 5.78 (t, 1 H, J=4.4 Hz), 6.79 (d, 2 H, J=9.0 Hz), 7.03 (dd, 1 H, J=2.3 & 8.2 Hz), 7.16 (d, 1 H, J=2.3 Hz), 7.28 (d, 1 H, J=8.2 Hz), 7.88 (d, 2 H, J=9.0 Hz). 4-[Methyl-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid (Compound 67) General Procedure N A solution of 4-[methyl-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid ethyl ester (Compound 66, 12 mg, 0.03 mmol) in 3.0 mL of ethanol was treated with 0.55 M KOH (1.0 mL). The solution was heated to 40 ° C. and stirred for 20 h. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, and extracted twice with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed in vacuo to give the title compound as a solid. 4-[Ethyl-(5,8,8-trimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid ethyl ester (Compound 68)