Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:32][CH:33]1[CH2:36][NH:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:35]3[CH2:36][CH:33]([OH:32])[CH2:34]3)=[O:17])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CC(O)C3)C2)cc1

Procedure:
0.3 g (0.7 mmol) of the compound from Example 12A, 0.2 g (2.18 mmol) of 3-hydroxyazetidine hydrochloride and 0.2 g (1.4 mmol) of potassium carbonate were initially charged in 6 ml of DMF and reacted in a single-mode microwave (Emrys Optimizer) at 150° C. for 30 min. The crude product was purified by preparative HPLC. Yield: 105 mg (40% of theory)
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7](O)=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:10])[CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: O=C(O)C(O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(O)c1ccc(F)cc1
Yield: 94.8 %

Procedure:
To a stirred solution of 4-fluoromandelic acid (1.0 g, 5.88 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.47 g, 12.34 mmol). The reaction mixture was refluxed for 1.5 hours. The reaction mixture was quenched with sat. ammonium chloride solution, filtered, concentrated to yield 0.87 g of 1-(4-fluorophenyl)ethane-1,2-diol.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8]C(=O)C2C=CC=CC=2)[CH2:6][CH2:5][N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1.Cl>>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:3][C@H:2]1[OH:1]
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O)c1ccccc1
Agent: Cl
Product: N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O

Procedure:
A mixture of 15 parts of trans-N-[3-hydroxy-1-(phenylmethyl)-4-piperidinyl]benzamide and 204 parts of a concentrated hydrochloric acid solution was stirred and refluxed for 18 hours. The reaction mixture was filtered and the filtrate was treated with sodium hydroxide. Upon cooling in an ice-bath, the addition of sodium hydroxide was continued till turbid. The product was extracted three times with 180 parts of methylbenzene. The combined extracts were dried, filtered and evaporated. The oily residue was dissolved in trichloromethane. The solution was washed with a small amount of water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified on triturating in petroleumether. The product was filtered off and dried, yielding 3.8 parts of trans-4-amino-1-(phenylmethyl)-3-piperidinol; mp. 74.1° C. (intermediate 72).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[C:10]([C:11]#[C:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH3:15])[CH3:14])=[CH:9][C:8]([C:24]2[C:29]([CH2:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:32][CH3:33])=[N:7][C:6]=1[CH3:34])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[C:10]([CH2:11][CH2:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])([CH3:15])[CH3:14])=[CH:9][C:8]([C:24]2[C:25]([CH2:32][CH3:33])=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][CH3:31])=[N:7][C:6]=1[CH3:34])[CH3:2]
Reactant: CCOC(=O)c1c(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(CCC(C)(C)O[Si](C)(C)C(C)(C)C)cc(-c2c(CC)cccc2CC)nc1C
Reaction time: 18 h

Procedure:
A mixture of 4-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-but-1-ynyl]-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (318 mg, 0.64 mmol) and 10% Pd/C (32 mg, 10 wt %) in MeOH (30 mL) is hydrogenated for 18 hours at 55 psi (Parr shaker). After filtering through celite, the filtrate is concentrated, and the residue purified by flash chromatography to give 4-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyl]-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: O=C(O)Cc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: O=C(O)Cc1ccccc1N1CCCC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 10.7 g of 2-(2-bromophenyl)acetic acid, 20 cm3 of pyrrolidine and 1.66 g of copper acetate is heated at 90° C. with stirring for 2 hours; after return to room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5 cm, height 55 cm), eluting with 1000 cm3 of 1,2-dichloroethane then with mixtures of 1,2-dichloroethane and methanol (proportions by volume): 1000 cm3 (98:2), 2000 cm3 (97:3), 1000 cm3 (96:4) and 1000 cm3 (95:5) and collecting fractions of 250 cm3. Fractions 21 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2 g of 2-[2-(1-pyrrolidinyl)phenyl]acetic acid are obtained in the form of an orange-coloured oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:5]1=[O:23])=[N+:2]=[N-:3].[OH-].[Na+].Cl>CO.O>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:5]1=[O:23])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccc(OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)N(CC(=O)O)C(=O)C(N=[N+]=[N-])CC2
Reaction time: 2 h

Procedure:
A suspension of 3-azido-1-ethoxycarbonylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (13.8 g) in methanol (75 ml) was treated with a solution of sodium hydroxide (1.9 g) in water (75 ml). The reaction mixture was stirred at 40°-45° for 2 hours. Water (100 ml) was added and the mixture was acidified with concentrated hydrochloric acid (10 ml) and extracted with methylene chloride (3×75 ml). The combined methylene chloride solutions were dried over magnesium sulfate and evaporated at reduced pressure to give 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 145°-147°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16]O)[C:11]([CH2:18][CH3:19])=[N:10]2)=[C:4]([CH3:20])[CH:3]=1.C(N(CC)CC)C.C(Cl)Cl.[OH:31][CH2:32][CH:33]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][NH:34]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][N:34]3[C@@H:33]([CH2:32][OH:31])[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35]3)[C:11]([CH2:18][CH3:19])=[N:10]2)=[C:4]([CH3:20])[CH:3]=1
Reactant: OCC1Cc2ccccc2CN1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CN1Cc2ccccc2C[C@@H]1CO
Temperature: 50 °C
Yield: 135.2 %

Procedure:
To an ice bath-chilled solution of [1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-yl-methanol (770 mg, 2.3 mmol) and triethylamine (0.382 ml, 2.7 mmol) in methylene chloride (10 ml) methane sulfonyl chloride (0.1 94 ml, 2.5 mmol) was added dropwise. After stirring the reaction at 0-5° C. for 30 minutes, (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (1.49 g, 9.1 mmol) and anhydrous N,N-dimethylformamide (2.2 ml) were added, and the resulting reaction mixture was heated (50° C. oil bath) for 21 hours. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate/water (10 ml of each). The aqueous phase was then extracted twice with equal-volume portions of fresh ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (1.5 g). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:5 in volume) afforded the title compound (0.45 g) as a light yellow oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[C:17](=O)[CH2:16][CH2:15]2.C([BH3-])#N.[Na+]>CO>[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[CH:17]([NH:4][CH:1]1[CH2:3][CH2:2]1)[CH2:16][CH2:15]2
Reactant: O=C1CCc2cccc(Cl)c21
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc2c1C(NC1CC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a cooled solution of 4.16 ml (60 mmol) of cyclopropylamine and 4.3 ml (75 mmol) of acetic acid, together with 5 g of 3 Å molecular sieves, in 80 ml of methanol, are added 5 g (30 mmol) of 7-chloro-2,3-dihydro-1H-inden-1-one. The reaction mixture is stirred for 4 hrs at reflux. The reaction mixture is then cooled to ambient temperature and 2.83 g (45 mmol) of sodium cyanoborohydride are slowly added. The reaction mixture is further stirred for 2 hrs at reflux. The solvent is removed under vacuum and 100 ml of water are then added to the residue and the pH is adjusted to 10 with sodium hydroxide. The watery layer is extracted three times with dichloromethane (3×50 ml); the combined organic layers are dried over magnesium sulphate and concentrated in vacuum to yield 5.6 g (80% yield) of 7-chloro-N-cyclopropyl-2,3-dihydro-1H-inden-1-amine as an brown oil (M+1=208).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Cl.[CH:10](N(C(C)C)CC)(C)C.COC(OC)N(C)C>C1(C)C=CC=CC=1>[CH3:10][S:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(S)n1
Reactant: CCN(C(C)C)C(C)C
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CSc1nccc(C)n1
Yield: 84.6 %

Procedure:
To 2-mercapto-4-methylpyrimidine·HCl (50.0 g, 0.307 mole) in toluene (750 mL), under argon, was added diisopropylethylamine (80.0 mL, 0.461 mole) followed by N,N-dimethylformamide dimethyl acetal (100 mL) and the mixture heated to reflux for 4 hours. Upon cooling, the reaction was concentrated in vacuo to an oil, dissolved in ether (400 mL), and washed with water (2×50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil which was vacuum distilled to give 2-methylthio-4-methylpyrimidine (36.4 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:12](/[CH:13]=[CH:14]/[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(C/C=C/c2cccnc2Oc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCc2cccnc2Oc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 60 mg (0.18 mmol) (E)-2-(4-Fluorophenoxy)-3-[3-(4-methoxyphenyl)-1-propenyl]-pyridine in 50 mL of ethanol was added 50 mg of 10%Pd/C, and the mixture was hydrogenated at 45 psi on a Parr Shaker Apparatus for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated to afford 50 mg (83% yield) of the title compound as a colorless oil. 1H NMR (CDCl3) d 1.92-2.06 (2H, m), 2.67 (2H, t, J=8 Hz), 2.75 (2H, t, J=8 Hz), 3.80 (3H, s), 6.82-7.14 (9H, m), 7.52 (1H, dd, J=2, 7 Hz), 7.99 (1H, dd, J=2, 5 Hz); thermospray MS: m/e 338 (M++1).
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C@@H:15]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=O)C(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Si:22]([O:21][C@H:15]1[CH2:16][CH2:17][CH2:18][C@@:19]2([CH3:20])[C@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][OH:7])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: C[C@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
The compound of Example 10D (6.45 g, 16 mmol) was dissolved in 30 mL of ether and cooled to −30° C.; 35 mL of a 1 N solution of lithium aluminum hydride in ether was added at a rate so as to maintain a constant temperature and a modest rate of gas evolution. The mixture was stirred at −30° C. for 10 minutes, and then it was warmed to 0° C. for 1 hour. The reaction was quenched by the careful addition of ethyl acetate (Caution! Vigorous gas evolution) and stirred for 10 minutes, then quenched with a solution of Rochelle's salt. The resultant mixture was partitioned between ethyl acetate and water; the organic phase was washed with brine and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 5% to 30% ethyl acetate in hexanes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[O:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]1)[C:5](O)=O.O=S(Cl)Cl.[NH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1[O:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]1)[C:5]#[N:26]
Reactant: CCCCCC1COC(c2ccc(C(=O)O)cc2F)OC1
Reactant: N
Solvent: O=S(Cl)Cl
Product: CCCCCC1COC(c2ccc(C#N)cc2F)OC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
As described in Example 9 4.44 gms. of 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoic acid are converted by SOCl2 into the acid chloride. After removing excess SOCl2 the residue obtained is added to aqueous ammonia and stirred for 4 hours at 20° C. The precipitated acid amide is filtrated by suction and dried. For conversion into the nitrile it is dissolved in 50 ml of pyridine and 10 ml of POCl3, then stirred at 20° C. for 20 hours and evaporated. Thus 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzonitrile is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][N:6]([CH3:10])[C:7](=[O:9])[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25](OC)(=[O:30])[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]([OH:30])=[CH:8][C:7](=[O:9])[N:6]([CH2:5][C:4]1[CH:11]=[CH:12][C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=1)[CH3:10]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)-N-methyl-acetamide (0.83 g, 3.57 mmol) in tetrahydrofuran (15 ml) was cooled to −78° C. and treated dropwise with 7.1 ml (7.1 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran. After 20 min, the mixture was treated dropwise with a solution of dimethyl oxalate (0.63 g, 5.35 mmol) in tetrahydrofuran (3 ml), stirred at −78° C. for 1 h and then at 5° C. for another 45 min. The reaction mixture was then quenched by the addition of 1 N hydrochloric acid and ethyl acetate. The organic phase was washed successively with water, saturated sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 85:15) gave 0.70 g (61% yield) of the title ester as clear oil. 1HNMR 400 MHz (C6D6) δ (ppm); mixture of rotamers: 2.01 and 2.49 (3H, 2 s, NCH3), 3.43 and 3.5 (3H, 2 s, OCH3), 4.0 and 4.4 (2H, 2 s, NCH2), 6.26 and 6.33 (1H, 2 s, CH), 6.62–7.2 (3H, m, aromatics). Anal. calcd for C13H13Cl2NO4: C, 49.08; H, 4.12; N, 4.40. Found: C, 49.38; H, 4.23; N, 4.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1OCC.[F:22]C1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:22]
Reactant: OB(O)c1ccccc1F
Reactant: CCOc1ccccc1-c1cc(OC)c(C(=O)O)cc1Cl
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2F)c(Cl)cc1C(=O)O
Yield: 70.9 %

Procedure:
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Example 15, Step A (3.72 g, 19.1 mmol) in N,N-dimethylformamide (20 mL) was added 2-fluorophenyl boronic acid (5.0 g, 35.7 mmol) and potassium carbonate (14.8 g, 107 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.688 g, 0.59 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on acid washed silica using a 10 to 50% gradient of diethyl ether in hexane to provide the desired title compound (3.8 g) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[CH:10][S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.C1C[O:35][CH2:34]C1>O.CN(C=O)C>[CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:34]=[O:35])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C1CCOC1
Reactant: CSc1ncnc2sccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncnc2sc(C=O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
4-(Methylthio)thieno[2,3-d]pyrimidine (J. Heterocycl. Chem. 1975, 12, 921-924) (1 g) in THF (5 mL) was added to a preformed solution of LDA (BuLi (1.6M in hexanes, 3.8 mL) and di-isopropylamine (0.85 mL)] in THF (20 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C. and then DMF (1.1 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature and stirred for a further 3 hours. The reaction mixture was diluted with water and the; product was extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM afforded the title compound as a white solid (1.17 g, 51%);
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([Br:14])[CH:5]=1)(=[O:3])[CH3:2]>Cl>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[Br:14]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1Br
Agent: Cl
Product: CC(=O)c1ccc(N)c(Br)c1

Procedure:
A solution of N-(4-Acetyl-2-bromo-phenyl)-acetamide (10.0 g, 39.05 mmol) in concentrated hydrochloric acid (200 mL) was stirred for 5 h under reflux. The reaction mixture was concentrated under reduced pressure. The residue was treated with a saturated aqueous solution of NaHCO3 (75 mL), extracted with CH2Cl2 (2×70 mL) and dried over Na2SO4. Evaporation leads to the product (8.35 g, 100%) which was used in step 2 without further purification.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[CH:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)C(=O)C2=CC=CC=C12.NN.Cl.[OH-].[Na+]>CO.C(OCC)C>[NH2:5][CH:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[CH:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(N5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 59.3 %

Procedure:
The 3-phthalimidocholestane (5.40 g, 9.75 mmol) was dissolved in 60 mL of methanol and anhydrous hydrazine (3.1 ml, 99 mmol) was added. The reaction mixture was stirred and heated at reflux under a nitrogen atmosphere for 4 hr. This mixture was then cooled to room temperature, 3.1 mL of concentrated HCl was added and the resulting mixture was heated at reflux overnight. Upon cooling to ambient temperature, 100 ml of diethyl ether and 50 ml of 1N NaOH were added (final pH of 10.1) and the layers were separated. The aqueous layer was extracted with 50 ml of diethyl ether and the combined organic fractions were filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol 90/10) to give 2.24 g of 3-aminocholestane in 59% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 50, N-methylpiperazine (0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were added N-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (0.045 ml, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=25:1 eluate was concentrated under reduced pressure to afford the title compound (86 mg, 0.17 mmol, 80%) as a white powder.
Reaction SMILES: Cl.[C:2]1(=N)[C:14]2[C:6]([C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][CH:4]=[CH:3]1.[NH4+:16].[OH-]>>[CH:2]1[C:14]2[C:13](=[NH:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: N=C1C=CC=C2C1=Cc1ccccc12
Agent: Cl
Agent: [OH-]
Product: N=C1c2ccccc2-c2ccccc21
Yield: 58 %

Procedure:
The fluorenone (4.0 g, 22.2 mmol) was stirred in an autoclave of 110° C. for three days in an ammonia atmosphere (7 to 8 atm). After the reaction, it was allowed to dissolve in diethyl ether. And, hydrogen chloride was blown into it. It was stirred for one hour at room temperature. The obtained suspension was filtered, and the filtrate was cleaned with the diethyl ether. With this, fluorenone imine hydrochloride (3.4 g, 71%) was obtained. This hydrochloride was allowed to decompose with an ammonia aqueous solution. And, it was recrystallized by using the methylene chloride and hexane. And, Fluoren-9-ylideneamine (2.3 g, 58%) was obtained.