Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CS(C)=O.[N:7]1([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[NH:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][N:22]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:32]I>O>[N:7]1([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[N:24]([CH3:32])[C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][N:22]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccc2[nH]c(-c3nnc4ccc(N5CCCCCC5)nn34)cc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(-c2nnc3ccc(N4CCCCCC4)nn23)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of potassium hydroxide (98 mg) and DMSO (5 ml), 6-azepan-1-yl-3-(1H-indol-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (501 mg) was added, and the mixture was stirred at room temperature for 30 minutes, and then combined with methyl iodide (0.15 ml) and then stirred for further 2 hours at room temperature. The reaction mixture was combined with water, and the resultant solids were collected by filtration, washed with a solvent a mixture of water and methanol, and then purified by silica gel column chromatography (eluent: chloroform: methanol=99:1). The resultant crude crystals were recrystallized from ethanol to obtain 6-azepan-1-yl-3-(1-methylindol-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (40 mg) as colorless crystals.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH3:48])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>CO>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:42][C:43]=1[CH3:48]
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(CCc2cc(O)c(=O)[nH]n2)ccc1F

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(4-fluoro-3-methylphenyl)ethynyl]pyridazine (Intermediate 29) except that the solvent mixture used for the hydrogenation was made up of ethyl acetate and methanol (1:1) and the final material was recrystallised from ethyl acetate.
Reaction SMILES: C=O.F[C:4](F)(F)[C:5]([O-:7])=O.C[NH2+]C1C=CC=CC=1.[CH2:18]1[CH2:28][C:26](=O)C2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(OCC)C>C1COCC1>[CH2:24]=[C:23]1[CH2:22][CH2:21][C:20]2[C:4](=[CH:26][CH:28]=[CH:18][CH:19]=2)[C:5]1=[O:7]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CCc2ccccc2C1=O
Yield: 92.4 %

Procedure:
To a suspension of paraformaldehyde (46.2 g, 1.54 mol) and N-methylanilinium trifluoroacetate (TAMA, 46.2 g, 1.54 mol) in 340 mL of dry THF was added α-tetralone (50 g, 0.342 mol). The solution was heated at reflux under nitrogen with stirring for 4 h, during which time the paraformaldehyde dissolved. After cooling, diethyl ether (700 mL) was added to the reaction mixture. The solvent was separated from the reaction mixture and washed with 500 mL of saturated sodium bicarbonate. Additional diethyl ether was added to the reaction mixture, separated and used to back extract the aqueous sodium bicarbonate layer. The combined organic layers were dried over magnesium sulfate, and the solution was then concentrated to a volume of approximately 300 mL and filtered through Celite. Complete evaporation of the ether yielded 50 g (90%) of crude 2-methylene-3,4-dihydronaphthalen-1-one, which was used immediately for the next reaction to prevent polymerization of the product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[CH:19]=C[C:16]([NH2:17])=[CH:15][C:14]=1[CH3:20].[N:21]1C=CC=CC=1.O>C(Cl)Cl>[Br:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16]([NH:17][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[N:21][CH:19]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: c1ccncc1
Reactant: Cc1cc(N)ccc1Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(NC(=O)c2c(F)cccc2F)ncc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a (0° C.) cooled and stirred solution of 2,6-difluorobenzoyl chloride (500 mg, 2.83 mmol) in DCM (10 mL) was added 4-bromo-3-methylaniline (632 mg, 3.40 mmol) followed by the addition of pyridine (275 μL, 3.40 mmol). The resulting mixture was warmed to room temperature and stirred overnight. Water (10 mL) was then added to the above mixture and extracted with DCM (3×20 mL). The combined organic layers were washed with 10% aq.HCl (10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 250 mg (28%) of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H, D2O exchangeable), 8.53 (s, 1H), 7.63 (s, 1H), 7.61-7.54 (m, 1H), 7.21 (t, J=7.0 Hz, 2H), 2.41 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH)+ Br79,81]
Reaction SMILES: O1CCCC1.C1([Li])C=CC=CC=1.[Br-].[OH:14][CH2:15][C:16]1[CH:41]=[CH:40][C:19]([CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][CH:17]=1.[CH2:42]([N:46]([CH2:55][CH2:56][CH2:57][CH3:58])[C:47]1[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=1)[CH2:43][CH2:44][CH3:45]>C1(C)C=CC=CC=1.O>[CH2:42]([N:46]([CH2:55][CH2:56][CH2:57][CH3:58])[C:47]1[CH:48]=[CH:49][C:50]([CH:51]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][OH:14])=[CH:41][CH:40]=2)=[CH:53][CH:54]=1)[CH2:43][CH2:44][CH3:45]
Reactant: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO)cc2)cc1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
In a stream of argon, to 40 ml of tetrahydrofuran was added 8.0 g of phenyllithium (19% solution in dibutylether) (18.1 mmol). To this mixture, 3.81 g (8.2 mmol) of 4-(hydroxymethyl)benzyltriphenylphosphonium bromide was added under cooling. After the mixture was stirred at the same temperature, 2.0 g (8.6 mmol) of 4-(dibutylamino)benzaldehyde was added thereto. The mixture was stirred at the same temperature for 1 hour. After the reaction mixture was added to water, extraction with toluene, washing with a saturated saline solution, and drying over anhydrous sodium sulfate were performed. Toluene was evaporated off. The residue was purified by silica gel column chromatography to give 2.37 g of a yellow liquid (yield: 85.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:33]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=1[O:41][CH3:42])[CH:12]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22].O>ClCCl>[CH3:40][O:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([O:41][CH3:42])[C:33]=1[C:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[C:12]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[C:14]([O:21][CH3:22])=[CH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1cccc(OC)c1C(c1c(OC)cccc1OC)C(c1c(OC)cccc1OC)c1c(OC)cccc1OC
Solvent: O
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=C(c1c(OC)cccc1OC)c1c(OC)cccc1OC)c1c(OC)cccc1OC
Reaction time: 18 h

Procedure:
To a solution of commercial triphenylmethylhexafluorophosphate (0.69 g, 1.8 mmol) in dichloromethane at room temperature was added a rotational isomer of 1,1,2,2-tetrakis(2′,6′-dimethoxyphenyl)ethane (0.90 g, 1.5 mmol). After stirring for 18 hours, water (10 mL) was added and the resulting mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate. Filtration and removal of the solvent gave tetrakis(2,6-dimethoxyphenyl)ethylene after washing with diethyl ether. {Note: Only one of the rotational isomers gives (5) upon treatment with trityl cation.}
Reaction SMILES: [CH3:1]/[C:2](/[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=[CH:3]/[CH2:4][CH3:5].[H][H]>C1(C)CCC(C(C)C)C(O)C1.[Pd]>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC/C=C(/C)c1ccc(C(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC1CCC(C(C)C)C(O)C1
Product: CCCC(C)c1ccc(C(=O)OC)cc1
Yield: 108.2 %

Procedure:
To a solution of (Z)-methyl 4-(pent-2-en-2-yl)benzoate (600 mg, 2.15 mmol) in menthol was added Palladium 10% on Carbon (340 mg, 0.3 mmol) and the mixture was hydrogenated at hydrogen gas pressure 4 atmosphere for 8 hours. The reaction mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to get methyl 4-(pentan-2-yl)benzoate (480 mg, 80%). LRMS (M+H+) m/z: calcd 206.13. found 206.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:24])[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:16]=2)[CH:3]=1.CO.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:24])[NH:17][CH:16]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2c(Cl)ccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(-c2c[nH]c3nccc(Cl)c23)cc(NC2CCCCC2)n1
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of Example 168c (82 mg, 0.164 mmol) in a mixture of 5 mL THF, 5 mL methanol was added a solution of 27 mg (0.654 mmol) lithium hydroxide in 0.5 mL water. After stirring for 16 hours the reaction mixture was concentrated to dryness and the residue suspended in water and a yellow solid was collected by filtration. Purified by silica gel flash chromatography (eluting with 10% ethyl acetate, 90% dichloromethane) provided the title compound as an off-white powder in 51% yield. MS (ESI+) m/z 361.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6) ppm 1.01-1.39 (m, 5H) 1.53-1.65 (m, 1H) 1.66-1.75 (m, 2H) 1.85-1.95 (m, 2H) 3.54-3.69 (m, 1H) 6.51 (s, 1H) 6.60 (s, 1H) 6.79 (d, 1H, J=7.54 Hz) 7.24 (d, 1H, J=5.16 Hz) 7.81 (s, 1H) 8.23 (d, 1H, J=4.76 Hz) 12.41 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH:9]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=1.[OH-].[K+]>[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][C:14]2[CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(Oc2ccc(C)cc2)cc1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
p-Bromotoluene (51 g), p-cresol (33 g) and potassium hydroxide (18.5 g) were mechanically stirred on a steam bath for 30 min., then heated at 190° C. for 1 hr. Copper bronze (2.0 g) was added and the heating continued for a further 1 hr. at 190° C., then 220° to 230° C. for 2.5 hr. After cooling, the residue was extracted into chloroform, filtered, and the extract washed with water, dried, evaporated and crystallised from ethanol to yield 4,4'-dimethyldiphenyl ether, m.p. 49°-50° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>ClCCl.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>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:14]#[C:13][CH2:12][OH:15])[CH:7]=[CH:8][N:9]=1
Reactant: C#CCO
Reactant: Brc1cccc2ccncc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCC#Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an inert atmosphere, 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of 8-bromoisoquinoline, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol, mp 138°-139° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:36][C:26]34[CH2:27][CH:28]5[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]5)[CH2:35]3)[CH2:33]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NC34CC5CC(CC(C5)C3)C4)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.078 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: Br[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)CCc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 1-bromo-4-(4-bromophenyl)-2-butanone (0.5 mmol) and imidazole (102 mg, 1.5 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was then diluted with ethyl acetate (15 mL), and the solution was washed with water (4×15 mL). The separated organic phase was dried over anhydrous Na2SO4, and then the solvent was removed under reduced pressure to afford a residue that was chromatographed on a silica gel column using ethyl acetate as mobile phase to give 4-(4-bromophenyl)-1-(1H-imidazol-1-yl)-2-butanone as a white solid (111 mg, 76%): mp 79-80° C., Rf=0.50 (ethyl acetate-methanol 4:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.70 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 4.65 (s, 2H), 6.81 (bs, 1H), 7.02 (d, J=7.6 Hz, 2H), 7.09 (s, 1H), 7.37-7.40 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 28.6, 40.9, 55.7, 120.1, 120.4, 130.0, 131.8, 138.0, 139.1, 202.3; HRMS (EI) Calcd. for C13H13BrN2O: 292.0211 (M+). Found: 292.0219.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([CH2:21][C:22](=O)[CH3:23])([O-:20])=[O:19].[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29]>C(O)C>[CH3:23][C:22]1[NH:25][C:26]([CH3:32])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:16]([C:15]2[C:9]3[S:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=2)[C:21]=1[N+:18]([O-:20])=[O:19]
Reactant: O=Cc1cccc2nc(-c3ccccc3)sc12
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1cccc2nc(-c3ccccc3)sc12

Procedure:
10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol of nitroacetone and 10 mmol of methyl 3-aminocrotonate are boiled in 20 ml of ethanol overnight, the mixture is concentrated and the residue is purified on a silica gel column (cyclohexane/ethyl acetate=6:4)
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>ClCCl.O>[OH:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@@H:20]1[C@@H:14]([CH2:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@H]4CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 8 h
Yield: 107 %

Procedure:
A solution of 19-nortestosterone (10.0 g, 35.5 mmol) in dichloromethane (100.0 ml) was mixed with the catalyst previously prepared from RhCl3.H2O (380 mg) and Aliquat-336® (800 mg) in water (10.0 ml) and dichloromethane (22.0 ml). The mixture was hydrogenated overnight at 20 psi. The product was washed twice with water (40 ml) and dried on Na2SO4. The catalyst was removed by flash-chromatography on silica gel with CH2Cl2 as eluant to give 10.5 g (92% yield) the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2Br)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].Cl[CH2:33]Cl.[C:35]([O-:38])(=[O:37])C.[Na+].[C]=O>CO>[CH3:33][O:38][C:35](=[O:37])[C:24]1[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][C:23]=1[CH:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:7](=[O:21])[N:6]1[CH3:22]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Reactant: CC(=O)[O-]
Reactant: ClCCl
Agent: [C]=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C

Procedure:
4-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-3-bromo-benzonitrile (intermediate 4)(643.0 mg, 1.31 mmol), 1.1-bis(diphenyl-phosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) (51.5 mg, 0.06 mmol) and sodium acetate (327.5 mg, 4.0 mmol) are suspended in methanol (21 mL) and treated with carbon monoxide at 5 bar and 100° C. for 19 h. The reaction mixture is concentrated, water and ethyl acetate are added and the phases are separated. The organic phase is washed twice with water, dried over MgSO4 and concentrated. Yield: 671 mg. ESI mass spectrum: [M+H]+=472; Retention time HPLC: 1.12 min (HPLC method Z018_S04).
Reaction SMILES: N#N.C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:29])[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23]C)[C:20]([O:25]C)=[C:19]([O:27]C)[CH:18]=2)[CH2:9][CH2:8]1)=[O:6].B(Br)(Br)Br.O>C(Cl)Cl.CO>[OH:23][C:21]1[CH:22]=[C:17]([CH2:16][CH2:15][C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)=[O:29])[CH:18]=[C:19]([OH:27])[C:20]=1[OH:25]
Reactant: COC(=O)C1CCC(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Agent: BrB(Br)Br
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(CCc1cc(O)c(O)c(O)c1)N[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 10.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve cis-{4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid methyl ester (75) (82 mg, 0.21 mmol) in anhydrous DCM (2.0 mL), cool the solution to −78° C. and add dropwise BBr3 (205 μL, 2.17 mmol). Stir the reaction mixture for 20 min at −78° C. and after slowly warming up for additional 2 h at rt Add dropwise water, followed by DCM and MeOH and remove solvent. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain cis-4-[3-(3,4,5-Trihydroxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid (76) (7 mg, 10%) as a colorless sticky solid. 1H NMR (400 MHz, CD3OD): 1.47-1.60 (m, 2H); 1.62-1.73 (m, 4H); 1.91-2.02 (m, 2H); 2.42 (t, 2H, J=7.6 Hz); 2.47-2.54 (m, 1H); 2.71 (t, 2H, J=7.3 Hz); 3.75-3.84 (m, 1H); 6.23 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:21][C:22]([CH3:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[CH:23]=[C:22]([CH3:29])[S:21][C:20]=2[CH3:19])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)c(C)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 2,5-dimethylthiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39 (dd, J=1.8 & 10.2 Hz, 1H), 7.24-7.16 (br m, 2H), 7.13 (dd, J=9.0 & 17.4 Hz, 1H), 6.77 (d, J=9.6 Hz, 1H), 5.98 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.55 (br s, 1H), 2.33 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@@H:14]([OH:16])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Br)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Yield: 84.7 %

Procedure:
To a solution of 4-((1R,2S)-1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (1.63 g, 2.9 mmol) in THF (60 mL) was added TBAF (3.2 mL, 3.2 mmol, 1 M solution in THF) at −50° C. After addition, the reaction mixture was allowed to warm to −20° C. gradually (about 1 h), then quenched by adding saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc. The EtOAc extracts were washed with water, brine, dried over Na2SO4 and filtered. Concentration provided a residue, which was purified by flash chromatography over silica gel to provide the title compound 4-((1R,2S)-1-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-chloro-3-methylbenzonitrile (1.10 g, 85%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.79 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.23 (d, J=8.6 Hz, 1H), 4.72 (dd, J=2.5, 8.6 Hz, 1H), 4.62 (m, 1H), 3.01 (d, J=3.5 Hz, 1H), 2.34 (s, 3H), 1.42 (d, J==6.3 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][CH:10]=1.[OH-:25].[Na+].[C:27](Cl)(Cl)=[O:28]>C(Cl)Cl.O>[CH3:17][C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH3:16].[C:27]([OH:28])([OH:8])=[O:25]
Reactant: O=C(Cl)Cl
Reactant: [OH-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)O

Procedure:
A 1000 ml four neck flask was fitted with a mechanical stirrer, a pH probe, aqueous caustic inlet tube and a Claisen adapter to which was attached a dry ice condenser and a gas inlet tube. To the flask was added 280 ml water, 340 ml methylene chloride, 1.4 ml triethyl amine (0.01 mole) and 57 g (0.25 mole) bisphenol-A. With stirring the pH was raised to 10 by addition of 25% aqueous sodium hydroxide, then 0.00925 mole (3.7 mole%) based upon mole of BPA of the acid or acid chloride end-capping agent was added. Phosgene was introduced into the flask at 1 g/min for 30 minutes (0.3 mole) with pH maintained at 9.5 to 11.5. The pH was adjusted to 11 at the end of the reaction. The resin layer was separated from the brine layer, then washed with 3 wt. % aqueous HCl until washing remained acidic, then twice with distilled water. The resin was then precipitated into 1500 ml of methanol in a Waring blender and washed with 500 ml more methanol.