Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[Br:53][C:54]1[CH:55]=[C:56]([CH2:61][NH2:62])[CH:57]=[CH:58][C:59]=1[F:60]>C(Cl)(Cl)Cl>[Br:53][C:54]1[CH:55]=[C:56]([CH2:61][NH:62][C:18]([C:17]2[CH:16]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:57]=[CH:58][C:59]=1[F:60]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To solution of the commercially available 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (200 mg, 0.63 mmol) in CHCl3 (5 mL) was added HOBt (90 mg, 0.67 mmol), EDCI (180 mg, 0.94 mmol), and triethylamine (0.2 ml, 1.4 mmol), followed by [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (151 mg, 0.62 mmol). The resulting mixture was allowed to stir at room temperature for 2 hours then quenched with saturated aq. NaHCO3 (1 mL) was added. The organic layer was separated, dried over Na2SO4 and evaporated to give a residue which was purified by Combiflash® chromatography eluting with hexane/ethyl acetate (95/5 to 70/30 over 15 min.) to give the title compound as white solid (265 mg, 80%). LC/MS: m/z, 505 (M+H), 2.81 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:26]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
An oven-dried 300 mL round-bottomed flask was charged with 2-methylphenol (15.0 g, 139 mmol), finely powdered K2CO3 (38.3 g, 277 mmol), and anhydrous DMF (60 mL) and the resulting solution was cooled to 0° C. Next, ethyl bromoacetate (18.5 mL, 167 mmol) was added dropwise at 0° C., and the reaction was stirred vigorously at room temperature for 1 h. The reaction mixture was cooled using an ice-water bath, water (180 mL) was added and the product was extracted twice with AcOEt (200 mL and 100 mL). The combined organics were sequentially washed with 2×100 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a slightly yellow oil which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 5% AcOEt/hexane—10% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to provide compound 10.1 as a colorless oil (29.3 g). 1H NMR (300 MHz) (CDCl3) δ 7.26-7.13 (2H, m); 6.90 (1H, t, J=7.3 Hz); 6.71 (1H, d, J=8.0 Hz); 4.63 (2H, s); 4.27 (2H, q, J=6.9 Hz); 2.30 (3H, s); 1.30 (3H, t, J=6.9 Hz).
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])=[CH:21][CH:20]=2)[N:7]=1)(=N)N.Br[CH:36]1[CH2:40][CH2:39][NH:38][C:37]1=[O:41].[OH-].[Na+].CO>CN(C=O)C.O>[CH3:18][C@H:13]1[CH2:14][O:15][CH2:16][CH2:17][N:12]1[C:10]1[CH:11]=[C:6]([CH2:5][S:4][CH:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[N:7]=[C:8]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])=[CH:23][CH:24]=2)[N:9]=1
Reactant: O=C1NCCC1Br
Reactant: C[C@H]1COCCN1c1cc(CSC(=N)N)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(CSC2CCNC2=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
1-[4-[4-(Carbamimidoylsulfanylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-phenyl-urea (125 mg) was dissolved in DMF (3 mL). The solution was then treated with 3-bromo-pyrrolidin-2-one (48 mg) followed by sodium hydroxide (42 mg) in water (1 mL), heated to 40° C. and left to stir for 24 h. The reaction was diluted in a little methanol and loaded onto a SCX-2 column (20 g), which was washed with methanol and the desired product eluted with 7N ammonia in methanol to give the desired material which was used without further characterisation.
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[C:9]([O:12][CH2:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:16]([C:44]2[CH:49]=[C:48]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=3)[C:47]([Cl:60])=[CH:46][C:45]=2[O:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][OH:66])[O:15]1)(=[O:11])[CH3:10]>ClCCl>[C:9]([O:12][CH2:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:16]([C:44]2[CH:49]=[C:48]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=3)[C:47]([Cl:60])=[CH:46][C:45]=2[O:61][CH2:62][CH:63]2[CH2:4][CH:64]2[CH2:65][OH:66])[O:15]1)(=[O:11])[CH3:10]
Reactant: CC[Zn]CC
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC/C=C\CO)cc2Cl)cc1
Solvent: ICI
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCC3CC3CO)cc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of diiodomethane (0.66 mL, 8.09 mmol) in dichloromethane (10 mL) was added diethyl zinc (1.1M solution in toluene, 3.7 mL, 4.05 mmol) at 0° C. and stirred for 15 min. The reaction mixture was cooled to −78° C. and ((2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-5-(4-ethoxybenzyl)-2-((Z)-4-hydroxybut-2-enyloxy)phenyl)tetrahydro-2H-pyran-2-yl)methyl acetate (46, 0.82 mg, 1.01 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture, slowly warmed up to −20° C. for 3 h. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and dried over magnesium sulfate. The organic layer was filtered and evaporated in vacuo and the residue was purified on a Biotage® apparatus (silica gel, 5 to 40% ethyl tetrahydrofuran in hexanes gradient) to give the title compound (47, 835 mg, 1.01 mmol, 100%, diastereomer in about 1:2 ratio) as colorless oil.
Reaction SMILES: C(OC[O:10][CH2:11][C@@H:12]([CH3:27])[CH2:13][CH2:14][CH2:15][C:16]([CH3:26])([CH3:25])[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Si:18]([O:17][C:16]([CH3:25])([CH3:26])[CH2:15][CH2:14][CH2:13][C@H:12]([CH3:27])[CH2:11][OH:10])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C[C@@H](CCCC(C)(C)O[Si](C)(C)C(C)(C)C)COCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](CO)CCCC(C)(C)O[Si](C)(C)C(C)(C)C
Yield: 76.7 %

Procedure:
Removal of BOM-protecting group in compound 3. (s)-6-(tert-Butyldimethylsilyloxy)-2,6-dimethyl-heptan-1-ol (4). 1st procedure. To a solution of compound 3 (1.5 g, 3.8 mmol) in ethyl acetate (10 mL) was added Pd/C (10%, 100 mg) at room temperature. The reaction mixture was stirred for 6 days under a continuous stream of hydrogen (from balloon) and Pd/C (100 mg in portions) was added 3 times per day. Then, the mixture was filtered and the solvent was evaporated under reduced pressure. The oily residue was chromatographed on silica gel using hexane/AcOEt (9:1) as an eluent yielding an oily alcohol 4 (0.80 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](Br)=[CH:8][S:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.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>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:9]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][S:7][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cscc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A solution of 4-bromothiophene-3-carboxylic acid methyl ester (500 mg, 2.3 mmol, 1.0 eq.) in THF (40 mL) was combined with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.7 g, 2.3 mmol, 1 eq.) under nitrogen. A solution of Na2CO3 (960 mg) in water (4.5 mL) was added, followed by the addition of PdCl2(PPh3)2 (80 mg, 0.1 mmol, 0.4 eq.). The resulting solution was stirred for 18 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (50 mL), then washed with saturated aqueous NaCl (2×100 mL). The organic layer was concentrated and the residue was applied onto a silica gel column and eluted with EtOAc/PE (1:30) to yield 4-(4-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.4 g) as a light yellow oil.
Reaction SMILES: CN1C2C=CC([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([CH2:42][CH:43]=[CH2:44])[C:20]5[C:25]([C:26]=4[CH:27]=3)=[CH:24][C:23](C3C=CC4N(C)C6C(C=4C=3)=CC=CC=6)=[CH:22][CH:21]=5)=CC=2C2C1=CC=CC=2.C1COCC1.[Cl:50][SiH:51]([Cl:53])[Cl:52]>C1(C)C=CC=CC=1>[Cl:50][Si:51]([Cl:53])([Cl:52])[CH2:44][CH2:43][CH2:42][N:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:27]=2
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCn1c2ccc(-c3ccc4c(c3)c3ccccc3n4C)cc2c2cc(-c3ccc4c(c3)c3ccccc3n4C)ccc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cl[Si](Cl)(Cl)CCCn1c2ccccc2c2ccccc21
Temperature: 60 °C

Procedure:
To a three-neck flask fitted with a reflux condenser and a dropping funnel were added the 3,6-bis(9-methylcarbazol-3-yl)-9-allylcarbazole (10 g), anhydrous THF (100 g), and platinum (0) 1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (250 mg of a 0.05% solution in anhydrous toluene). Then, trichlorosilane (30 g) was slowly added. When the addition of trichlorosilane was completed, the mixture was heated to 60° C. and maintained at that temperature for two hours. Then, the mixture was distilled at 0.02 torr to remove volatiles and gave 9-(3-trichlorosilylprop-1-yl)carbazole with a yield of about 5.6 g, at a concentration of about 90% by weight. 1 H NMR (CDCl3) δ 8.53 (d, 2 H, J=1.5 Hz); 8.46 (d, 2 H, J=1.2 Hz); 8.21 (d, 2 H, J=7.8 Hz); 7.87 (m, 4 H); 7.48 (m, 8 H); 7.27 (m, 2 H); 6.10 (m, 1 H); 5.40 (d, 1 H, J=9.0 Hz); 5.14 (d, 1 H, J=15.9 Hz); 5.00 (m, 2 H); 3.91 (s, 6 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[N:6][CH:7]=1.[Cl:16][C:17]([Cl:22])([Cl:21])[C:18](Cl)=[O:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][C:17]([Cl:22])([Cl:21])[C:18]([C:14]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:19]
Reactant: Cc1cnc(C(=O)Cn2cccc2)cn1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(C(=O)Cn2cccc2C(=O)C(Cl)(Cl)Cl)cn1
Reaction time: 8 h

Procedure:
To a chilled (0° C.) solution of 1-(5-methylpyrazin-2-yl)-2-(1H-pyrrol-1-yl)ethanone (318 mg, 1.58 mmol) in CH2Cl2 (21 mL) was added 2,2,2-trichloroacetyl chloride (400 μL, 3.56 mmol). The solution was allowed at room temperature and stirred until complete (overnight, monitored by LCMS). A chilled saturated solution of NaHCO3(15 mL) was then added and the mixture extracted with CH2Cl2 (3×15 mL). The organic were dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that is purified by flash chromatography (Biotage SP4, 4 g cartridge, gradient 1 CV hexane, 0-50% EtOAc in hexanes 10 CV; 50-100% 3CV). The compound 2,2,2-Trichloro-1-{1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrol-2-yl}ethanone was isolated as a crystalline solid (260 mg, yield 38%). 1H-NMR (400 MHz, CDCl3): δ 2.70 (s, 3H), 5.91 (2H, s), 6.45 (dd, 1H, J 4.4, 2.5, Hz), 7.02 (dd, 1H, J 2.4, 1.6 Hz), 7.64 (dd, 1H, J 4.4, 1.5 Hz), 8.53-8.55 (m, 1H), 9.15 (d, 1H, J 1.3 Hz).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:31]=[CH:30][C:29](=[O:32])[N:28]([CH2:33][CH:34]=O)[C:27]=2[N:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:8][N:7]([CH2:34][CH2:33][N:28]2[C:29](=[O:32])[CH:30]=[N:31][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[N:36][C:27]2=3)[CH2:6][CH:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: CO[C@H]1CNC[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CC(CN4C(=O)c5ccccc5C4=O)CC(OC)C3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To cis-2-{[(3RS,5SR)-5-(methyloxy)-3-piperidinyl]methyl}-1H-isoindole-1,3(2H)-dione (125 mg, 0.43 mmol) in MeOH (1 ml) and CHCl3 (5 ml) was added [6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (100 mg; 0.50 mmol) and the reaction was allowed to stir at room temperature under N2 for 4 hours. Na(OAc)3BH (210 mg; 1.0 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The reaction was partitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (20 mL), the aqueous layer was further extracted with CH2Cl2 (20 mL), and the combined organic layers were dried over Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (10 mg; 55%) as a colorless oil.
Reaction SMILES: [F:1][CH2:2][C:3]1[C:4]([C:9]([O:11]C)=O)=[N:5][CH:6]=[CH:7][N:8]=1.[CH2:13]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[C:24]([O:33][CH3:34])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])[NH2:20])[CH:14]([CH3:16])[CH3:15].C[O-].[Na+].Cl>CO>[CH2:13]([C:17]1[CH:18]=[C:19]([NH:20][C:9]([C:4]2[C:3]([CH2:2][F:1])=[N:8][CH:7]=[CH:6][N:5]=2)=[O:11])[CH:21]=[CH:22][C:23]=1[C:24]([O:33][CH3:34])([C:25]([F:28])([F:26])[F:27])[C:29]([F:30])([F:31])[F:32])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1nccnc1CF
Reactant: COC(c1ccc(N)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(c1ccc(NC(=O)c2nccnc2CF)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Yield: 66.3 %

Procedure:
Methyl 3-fluoromethylpyrazine-2-carboxylate (390 mg, 2.29 mmol) and 3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (750 mg, 2.29 mmol) were stirred, followed by adding a 28% by weight methanol solution of sodium methoxide (4.4 g, 22.9 mmol), heating at 60° C. for 3 hours while stirring, pouring into a diluted HCl solution, extracting with ethyl acetate and washing with water. The reaction solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.71 g of the desired compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH:30]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH:30]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)C(=O)O
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of 98 (124 mg, 0.31 mmol) in THF/water, 2:1 (9 mL) was added lithium hydroxide monohydrate (26 mg, 0.62 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organics were dried and evaporated to yield the title compound (65 mg, 0.17 mmol, 55%) as a white solid. Mp 128-132° C. [α]D20 +36.8 (c. 0.1, EtOH). 1H NMR (CD3OD, 300 MHz): δ 8.71 (d, J=8.1 Hz, 1H, ArH4″); 8.66 (d, J=8.4 Hz, 1H, ArH3″); 7.79 (s, 1H, ArH1″); 7.76 (s, 1H, ArH10″); 7.51 (m, 5H, ArH7″, ArH6″, ArH5″, ArH2″ and ArH1″); 7.32 (m, 2H, Ar′H); 4.76 (dd, J=5.1, 9.0 Hz, 1H, H2); 3.29 (dd, J=4.8, 13.5 Hz, 1H, H3a); 3.03 (dd, J=8.7, 13.5 Hz, 1H, H3b); 1.95 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 384 (50%) [MH+]. HRMS calcd for C25H22NO3 384.1600, found 384.1628.
Reaction SMILES: Cl[C:2]1[C:3]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:22][N:23]1[CH:27]=[N:26][C:25]([CH2:28][OH:29])=[N:24]1.[H-].[Na+]>CN(C=O)C.O>[CH2:18]([N:17]([CH2:20][CH3:21])[C:3]1[C:2]([O:29][CH2:28][C:25]2[N:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=[C:5]2[CH:4]=1)[CH3:19]
Reactant: Cn1cnc(CO)n1
Reactant: CCN(CC)c1cc2nnc(-c3ccccc3)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1cc2nnc(-c3ccccc3)n2nc1OCc1ncn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-(6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-7-yl)-N,N-diethylamine (180 mg, 0.33 mmol) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (68 mg) in dry DMF (5 ml) was added sodium hydride (60% dispersion in oil, 34 mg, 0.36 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3×25 ml). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The solid was recrystallised from ethyl acetate, and collected by filtration to afford the title pyridazine (81 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ1.08 (6 H, t, J=8.5 Hz), 3.31 (4 H, q, J=8.5 Hz), 3.87 (3 H, s), 5.50 (2 H, s), 7.22 (1 H, s), 7.47-7.59 (3 H, m), 8.37 (2 H, d, J=8.5 Hz), 8.51 (1 H, s). MS (ES+) 379 [MH]+.
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: Oc1cccc(C(F)(F)F)c1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2cccc(C(F)(F)F)c2Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 85 by using 2-phenoxy-3-trifluoromethyl-phenol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 57 mg (10%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:10]1([CH3:42])[CH3:41])(C(C)(C)C)(C)C>C(O)C.C1C=CC=CC=1.Cl>[CH3:42][C:10]1([CH3:41])[C@@H:9]([OH:8])[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:32]([CH3:40])([CH2:33][CH2:34][C:35]=12)[C@@H:18]([C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH:16]=3
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A mixture of 3β,24-bis(tert-butyldimethylsilyloxy)-4,4-dimethylchola-5,7-diene (18.8 g) in 99.9% ethanol (375 ml), benzene (55 ml) and concentrated hydrochloric acid (55 ml) is heated to reflux for 4 hours. After standing overnight at room temperature, the reaction mixture is concentrated under reduced pressure. Crystallization of the remanens from ethanol/water gives 8.44 g of the title compound. Melting point: 203-208° C. 1H-NMR (CDCl3, 400 MHz): δ=5.36 (1H, s); 3.62 (2H, m); 3.23 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[S:11]C#N.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[SH:11]
Reactant: Cc1cc(SC#N)c(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(S)c(C)c(C)c1O
Temperature: 0 °C
Yield: 103.4 %

Procedure:
2,3,5-Trimethyl-4-hydroxyphenylthiocyanate (2 g, 10.35 mmol) was dissolved in 100 mL of anhydrous ether containing 25 mL of anhydrous tetrahydrofuran. This solution was added dropwise over 1 h to 100 mL of anhydrous ether containing LiAlH4 (0.9 g, 24 mmol) at room temperature. After a further hour at 20° C., the unreacted LiAlH4 was destroyed by cooling the heterogeneous mixture to 0° C. and adding moist ether (50 mL), H2O (50 mL), and 1 N HCl (50 mL). A further 50 mL of water was added and the organic phase was separated and washed with water (2×50 mL), NaHCO3 solution (2×50 mL), water (2×50 mL), and saturated NaCl (50 mL). The organic phase was dried over anhydrous MgSO4 and filtered and the solvent removed under reduced pressure. Silica gel column chromatography with 5% ethyl acetate in hexane gave 1.8 g (90%) of 2,3,5-trimethyl-4-hydroxybenzenethiol as a white powder, mp 86° C. [Lit. 1mp 86° C.].
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=O)[C:16]#[C:17][CH2:18][O:19][CH3:20])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][NH2:30].O>CCO>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[C:17]([CH2:18][O:19][CH3:20])[NH:30][N:29]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COCC#CC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: COCc1cc([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)n[nH]1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A stirred solution of 13E (150 mg, 0.399 mmol) in EtOH (2 mL) was treated with hydrazine (0.116 mL, 2.397 mmol), and stirred overnight at 75° C. Upon cooling, water was added, the mixture was stirred for 1 h, the resulting white solid was collected by filtration and air dried to yield 13F (125 mg, 80% yield). MS (ES): m/z=390.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (d, 4H, J=7.0 Hz); 7.18-7.25 (m, 4H); 7.14 (t, 2H, J=7.3 Hz); 5.92 (s, 11H); 4.35 (s, 2H); 3.58 (s, 4H); 3.30 (s, 3H); 2.44-2.55 (m, 2H); 1.89-2.01 (m, 4H); 1.23-1.50 (m, 4H).