Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccc(F)cc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5′-Amino-5,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 ml), 48% aqueous hydrobromic acid (40 ml) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 ml) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 ml). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 ml), water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography [silica gel, 2-6% EtOAc/isohexane (containing 0.5% methanol)] gave the title compound as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ7.13 (1H, dd, J9, 9 Hz), 7.19-7.23 (2H, m), 7.52-7.60 (2H, m), 7.81 (1H, dd, J8, 5 Hz).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([OH:30])=O)[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:46][CH2:47][CH2:48][S:49]([OH:52])(=[O:51])=[O:50]>>[C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:46][CH2:47][CH2:48][S:49]([OH:52])(=[O:51])=[O:50])=[O:30])[CH:25]([CH3:26])[CH3:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NCCS(=O)(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)NCCS(=O)(=O)O)C(C)C
Yield: 26.8 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (1.28 g) and taurine (1 g), N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]taurine (400 mg) was obtained as powder according to a similar manner to that of Example 32.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:29]([C:28]1[CH:27]=[C:26]([CH:34]=[CH:33][CH:32]=1)[C:24]#[N:25])[O:14]2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (61 mg, 0.257 mmol) and K2CO3 (178 mg, 1.29 mmol) in acetone (3 mL) was added 3-cyanobenzoyl chloride (43 mg, 0.257 mmol). The reaction vessel was sealed and heated to 60° C. for 2 d. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 6 mg (7%) of 3-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile. Rf=0.33 (50% EtOAc/hexanes).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][CH2:10][N:11]3[C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[CH3:28])=[N:4][N:3]=[N:2]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][CH2:17][C:16]([N:11]1[C:12]2[C:7](=[C:6]([C:5]3[N:4]=[N:3][N:2]([CH2:31][C:32]4[CH:33]=[C:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH:35]=[CH:36][CH:37]=4)[N:1]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:29]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn[nH]4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn(Cc5cccc(NC(=O)OC(C)(C)C)c5)n4)cccc32)c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
A mixture of 1-(5-(1H-tetrazol-5-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one (0.16 g, 0.409 mmol), tert-butyl 3-(bromomethyl)phenylcarbamate (0.152 g, 0.531 mmol) and K2CO3 (0.113 g, 0.817 mmol) in DMF (1 mL) was stirred at 80° C. for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (96 mg, 40% yield). LCMS, [M+H]+=597.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1.Cl.C([O-])([O-])=[O:20].[Na+].[Na+]>OO>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[OH:20])=[O:17])=[CH:10][CH:11]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(C(=O)c2cnccc2Cl)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCc1ccc(C(=O)c2cnccc2O)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Next, to a solution of (4-chloropyridin-3-yl)-(4-ethylphenyl)methanol (3.2 g, 0.0129 mol) in chloroform (45 mL), Dess-Martin periodine (6.5 g, 0.0154 mol) was added under ice cooling and the reaction mixture was stirred at room temperature for 5 hours. After filtration to remove the precipitated insoluble materials, the filtrate was washed with 1M NaOH (40 mL) and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by NH silica gel chromatography (ethyl acetate) to give 4-chloro-3-(4-ethylbenzoyl)pyridine (3.4 g) as a yellow oil. A mixture of 4-chloro-3-(4-ethylbenzoyl)pyridine (3.4 g), 3M HCl (35 mL) and 30% H2O2 (2 drops) was heated under reflux for 6.5 hours. After cooling to room temperature, the reaction mixture was neutralized with Na2CO3. The resulting precipitate was filtered and washed with ethyl acetate to give 3-(4-ethylbenzoyl)-4-hydroxypyridine (2.9 g, 92% for 2 steps) as a light-yellow crystal.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])(C1C=CC(C)=CC=1)(=O)=O.[NH2:54][C:55]1[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=[C:59]([CH2:61][OH:62])[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:62][CH2:61][C:59]1[CH:60]=[C:55]([NH:54][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=1
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(CO)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred mixture of methyl 1-(tosyloxy)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265b)(700 mg, 0.890 mmol) and (5-amino-1,3-phenylene)dimethanol (26) (150 mg, 0.978 mmol) in anhydrous DMF (2.0 ml) was added potassium carbonate (184 mg, 1.334 mmol). The reaction was stirred at 80° C. overnight. The mixture was cooled to room temperature, quenched with water and extracted with 10% Methanol/Methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with 5→15% MeOH/CH2Cl2) to give methyl 1-(3,5-bis(hydroxymethyl)phenylamino)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265c) (285 mg, 42%). 1H NMR (400 Hz, CDCl3): δ 6.62 (s, 1H), 6.51 (s, 2H), 4.52 (s, 4H), 3.72 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.61 (m, 48H), 2.94 (s, 2H), 2.63 (s, 1H), 2.57 (t, J=6.4 Hz, 2H); MS (m/z), found 790.4 (M+Na)−.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=O>C1COCC1>[Br:16][C:13]1[CH:12]=[C:3]([CH2:4][NH:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])[C:2]([NH2:1])=[N:15][CH:14]=1
Reactant: CN(C)CCNC(=O)c1cc(Br)cnc1N
Solvent: C1CCOC1
Product: CN(C)CCNCc1cc(Br)cnc1N
Yield: 24.5 %

Procedure:
2-Amino-5-bromo-N-(2-dimethylamino-ethyl)nicotinamide (2.15 g, 7.48 mmol) was added to a BH3 solution (37.5 mL of a 1 M solution in THF, 37.5 mmol), and the mixture was heated to reflux for 6 h. After cooling, the solvent was removed in vacuo. The residue was dissolved in MeOH (20 mL). Concentrated HCl (3 mL) and H2O (3 mL) were added and the mixture was heated to reflux for 2 h. The solvent was then concentrated and the aqueous residue was basified to pH 12 with aqueous NaOH (6 N). The resulting aqueous suspension was extracted with CH2Cl2 (3×60 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.50 g, 25%) as a colorless oil: MS (ESI) m/e 273 (M+H)+.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[OH:30])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:28][C@:18]12[CH2:19][C:20](=[O:50])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]/[C:17]/2=[N:29]\[OH:30]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 80 %

Procedure:
The title compound II-aq was prepared in 80% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (I-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone/CH2Cl2 60/20/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS: δ 10.72 (1H, s), 5.35 (1H, s), 3.12 (1H, dd), 2.85-1.09 (18H, m), 0.94 (3H, s), 0.78 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH3:43])[O:35][CH:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]2)[CH2:33][O:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:31]1([CH3:43])[O:35][C@H:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH:42][C:27]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:12]([C:15]4[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=4)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]3)=[O:28])=[N:38]2)[CH2:33][O:32]1
Reactant: CC1(C)OCC(Cn2ccc(N)n2)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (59.14 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (91.2 mg, 74.68%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45Cl2N5O2S+H [(M+H)+]: 610.2346. found: 610.2345.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:19])([CH3:18])[CH3:17])=O)C1C=CC=CC=1.Cl>CCO.[Pd]>[NH:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:19])([CH3:18])[CH3:17]
Reactant: CC(C)(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(O)[C@@H]1CCCN1
Yield: 98.2 %

Procedure:
A mixture of (S)-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidine-1-carboxylic acid benzyl ester (0.727 g, 2.76 mmol) and Pd/C (10%, 72 mg) in EtOH was shaken with H2 in a Parr bottle under 50 psi. After 12 h the reaction mixture was filtered through celite. HCl (9 mmol, 1 N in Et2O) was added to the filtrate, the filtrate was then concentrated to give a white solid (350 mg, 98%).
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:11]([C:23]1[S:24][C:25]([CH:3]=[O:4])=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCc1cccs1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 75.9 %

Procedure:
In a 1 liter-four-necked flask, 93.7 (1.28 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 107.4 g (7.00×10-1 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 160 g (6.35×10-1 mol) of 2-dodecylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2.5 hours at 60° C. After the reaction, the reaction mixture was poured into 2 liters of iced water, subjected to 3 times of extraction with 500 ml of chloroform and washed 6 times with 500 ml of water. The organic layer was dried on CaCl2, followed by distilling-off of the solvent to obtain 237 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 135 g of a product (yield: 75.9%). b.p.: 160° C./0.6 mmHg
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH3:20])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3].[C:21]([O:25][C:26](=[O:37])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:21]([O:25][C:26](=[O:37])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:2]([C:4]2[C:5]([CH3:20])=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:36])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc(O)ccc1SCC(=O)OC(C)(C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To 0.118 g (0.39 mmol) of the above prepared [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) and 0.100 g (0.39 mmol) of (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid tert-butyl ester (see below example 20C]), dissolved in 2.0 ml of abs. acetone, were added successively 0.065 g (0.39 mmol) of KI and 0.154 g (0.47 mmol) of Cs2CO3. The reaction was allowed to proceed for 2 h at ambient temperature, when TLC still indicated large amounts of starting material. Therefore, stirring was continued over night at 40° C. Pouring onto crashed ice, extraction with AcOEt, filtration over Celite, washing of the organic layer with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), produced 0.143 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:22][CH3:23])[C:20]#[CH:21]>C(NCC)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.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:21]#[C:20][CH2:19][O:22][CH3:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOC
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COCC#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
10.0 g (26.7 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 140 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 40 mg of copper(I) iodide and 3.4 ml (40.3 mmol) of methyl propargyl ether in 100 ml of diethylamine were heated to boiling under reflux for 3.5 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 154°-156°.
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]1OCC[O:14]1)([O:3][CH2:4][CH3:5])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]=[O:14])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1sccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)CSc1sccc1C=O

Procedure:
To a solution of 2-(carboethoxymethylthio)-3-(1,3-dioxolan-2-yl)thiophene (from step b) in acetone (200 mL) was added p-toluenesulfonic acid (761 mg, 4.0 mmole) at RT. After 18 hr the mixture was concentrated. The residue was taken up in Et2O, washed with saturated NaHCO3, H2O (2×), dried (MgSO4), and concentrated under reduced pressure to give the title compound as an oil which was sufficiently pure for use in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[BH4-].[Na+]>CO.ClCCl>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([OH:14])[CH3:13])[CH2:3]1
Reactant: 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
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](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

Procedure:
To a stirred solution of 3α-hydroxy-5α-pregnan-20-one (3.2g, 318.5 g/m, 10 mmol) in 160 mL of methanol and 30 mL of dichloromethane at room temperature was slowly added sodium borohydride (3.3 g, 37.8 g/m, 87 mmol) over a period of 2 h. The mixture was stirred for an additional hour and then poured into ice cold water (700 mL) and extracted three times with ether. The combined organic phase was washed several times with water, dried over magnesium sulfate and concentrated to a white solid (2.35 g, 320.5 g/m, 7.3 mmol, 73%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12](Cl)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2].[CH3:23][NH:24][CH3:25]>>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2]
Reactant: CNC
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N(C)C)c2Cl)c1O
Temperature: 110 °C

Procedure:
A mixture of 0.60 g (1.7 mmol) of 1-ethyl-4-(2,3-dichloro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole and 8 mL of 40 percent aqueous dimethylamine was placed in a pressure reactor and heated at 110° C. for 24 hours. It was then allowed to cool and was concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution obtained was washed with 1N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain about 0.50 g of a yellow foam. This was crystallized from ethanol to obtain, after drying for 24 hours at 50° C., 0.17 g of the title compound as an off-white solid melting at 227°-228° C. with decomposition.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH:10]([CH2:13][OH:14])[CH2:11]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH:1]1([CH2:7][N:8]2[CH2:9][CH:10]([CH2:13][OH:14])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC(CO)CNCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: OCC1CN(CC2CCCCC2)C1

Procedure:
To 100 mL of carbon tetrachloride add 19.2 g (0.1 mol) of 2-[(cyclohexylmethylamino)methyl]-1,3-propanediol, 26.2 g (0.1 mol) of triphenylphosphine, and 11 g (0.1 mol) of triethylamine. Monitor the reaction by thin-layer chromatography. Upon completion extract twice with 50 mL of 1N aqueous HCl. Add 1N NaOH to the aqueous portion until basic and extract twice with 100 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>O1CCCC1>[CH2:9]([O:8][C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[N:7]=1)[CH3:10]
Reactant: CCOc1cc(C)nc(Cl)n1
Reactant: c1cn[nH]c1
Solvent: C1CCOC1
Product: CCOc1cc(C)nc(-n2cccn2)n1
Yield: 53.9 %

Procedure:
In anhydrous tetrahydrofuran, 173 mg of 2-chloro-4-ethoxy-6-methylpyrimidine was substituted with 68 mg of pyrazole. The reaction mixture was treated according to the procedure of Example 5 to yield 110 mg of 4-ethoxy-6-methyl-2-(1-pyrazolyl)pyrimidine, an oily compound.