Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.C(O[CH:7]([CH:19]1[C:28]2[N:27]=[CH:26][C:25]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11]CC)=O)C>C(N(CC)CC)C>[N:30]1([CH2:29][C:25]2[CH:24]=[C:23]3[C:28]4[N:27]([CH:26]=2)[C:9](=[O:11])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:19]=4[CH2:20][CH2:21][CH2:22]3)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)C(C(=O)OCC)C(OCC)C1CCCc2cc(CN3CCOCC3)cnc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c3c(cc(CN4CCOCC4)cn3c1=O)CCC2
Reaction time: 12 h
Yield: 101.2 %

Procedure:
A 250 mL round bottom flask equipped with a condenser is charged with ethanol (150 mL), triethylamine (0.93 mL) and diethyl 2-(ethoxy(3-(morpholin-4-ylmethyl)-5,6,7,8-tetrahydroquinolin-8-yl)methyl)malonate (Preparation 17, 750 mg). The solution is heated to reflux. After 12 h, the mixture is concentrated to give a yellow solid, which is purified by flash chromatography (silica gel, 6% MeOH: methylene chloride) to give 603 mg of the title compound. Physical characteristics: 1H NMR (DMSO-d6): δ9.02, 8.04, 7.58, 4.24, 3.59, 3.57, 3.01, 2.88, 2.42, 1.89, 1.30; 13C NMR (DMSO-d6): δ165.3, 154.1, 141.6, 138.3, 134.4, 132.8, 126.9, 125.3, 110.0, 104.3, 66.1, 59.7, 59.1, 52.9, 29.2, 27.8, 20.7, 14.3; IR (KBr) 3079, 3037, 2958, 2931, 2913, 2850, 2828, 1731, 1679, 1647, 1628, 1600, 1509, 1462, 1450, 1297, 1270, 1251, 1227, 1206, 1114, 1097, 1079; HRMS m/z 357.1818.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([S:14]([NH:17][C:18]2[C:19]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:20]([F:28])[C:21]3[N:25]=[CH:24][N:23]([CH3:26])[C:22]=3[CH:27]=2)(=[O:16])=[O:15])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[F:28][C:20]1[C:21]2[N:25]=[CH:24][N:23]([CH3:26])[C:22]=2[CH:27]=[C:18]([NH:17][S:14]([C:11]2([CH2:10][CH2:9][OH:8])[CH2:13][CH2:12]2)(=[O:16])=[O:15])[C:19]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=1[F:37]
Reactant: Cn1cnc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO[Si](C)(C)C(C)(C)C)CC3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO)CC3)cc21
Reaction time: 2 h
Yield: 82.1 %

Procedure:
1-(2-(Tert-butyldimethylsilyloxy)ethyl)-N-(4-fluoro-5-(2-fluoro-4-iodophenylamino)-1-methyl-1H-benzo[d]imidazol-6-yl)cyclopropane-1-sulfonamide (39 mg, 0.06 mmoles) was dissolved in THF (0.5 ml) and aqueous hydrochloric acid (1.2 N, 0.5 ml) was added at 0° C. After stirring the reaction mixture for two hours, a saturated aqueous solution of sodium bicarbonate (5 ml) was added. The mixture was extracted with EtOAc (3×5 ml). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography using MeOH/CHCl3 (1/9) yielding to the title compound (27 mg, 83%). m/z=549 [M+1]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[CH3:23][O:24][C:25](=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C.CN(C)C=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH2:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17][CH2:18][N:12]1[C:4]1[CH:3]=[C:2](/[CH:27]=[CH:26]/[C:25]([O:24][CH3:23])=[O:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C=CC(=O)OC
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1.5 g, 4.86 mmol), acrylic acid methyl ester (0.88 ml, 9.7 mmol), triethylamine (6 mL) and N,N-dimethylformamide (6 mL), bis(tri-tert-butylphosphine)palladium(0) (124 mg, 0.243 mmol) was heated with stirring in a 20 mL of microwave process vial for 30 minutes at 100° C. under argon. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by flash column to afford 1.41 g of product as a white solid (yield was 81%). MS obsd. (ESI+) [(M+H)+] 359.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[N:12])=[C:4](Cl)[N:3]=1.CO.C1CCCCC1.CCOC(C)=O>CN(C=O)C.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[N:12])=[CH:4][N:3]=1
Reactant: Cc1c(C#N)c(N)nc(Cl)c1C#N
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: CO
Product: Cc1c(C#N)cnc(N)c1C#N
Yield: 86 %

Procedure:
Hydrogenolysis of 4 (10.0 g, 52.0 mmol) in DMF (150 mL)-MeOH (75 mL) containing 5% Pd on BaCO3 (10.0 g) was carried out in a Parr shaker with H2 pressure kept near 3.5 kg/cm2 (50 psi) for six hours. The mixture was then filtered (Celite mat), and evaporated to dryness (final conditions <1 mm, bath to 45° C.) The residue containing Ba salts which separated during the evaporation was stirred with H2O (100 mL) to give the H2O-insoluble product (7.74 g). Recrystallization from EtOH (800 mL) then gave pure 6, mp 222°-223° C., in 86% yield (7.1 g); homogeneous by TLC (cyclohexane-EtOAc, 1:1); 1H NMR (Me2SO-d6) δ2.50 (s, CH3), 7.82 (s, NH2), 8.50 (s, C2 --H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:19][C:18]=1[OH:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.O>ClCCl>[Si:1]([O:33][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Yield: 108.7 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (579 mg, 3.84 mmol) in dichloromethane (10 cm3) was added to a stirred solution of benzyl 4-benzyloxy-3-hydroxy-benzoate (642.3 mg, 1.92 mmol) and imidazole (327 mg, 4.80 mmol) in dichloromethane (15 cm3). A thick precipitate formed immediately. After 1 h the mixture was poured into water (50 cm3). The layers were shaken and separated and then the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined extracts were washed with brine (50 cm3) then dried (Na2SO4) and evaporated to a pale yellow oil. This was taken up in 20% ethyl acetate in petroleum ether and filtered through a plug of silica. Evaporation of the filtrate gave the title compound as a pale yellow oil (936 mg) which was used immediately for the next step.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C2C=CC=CC=2N=N1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22]1[C:26]([CH2:27]O)=[C:25]([CH:29]([CH3:31])[CH3:30])[O:24][N:23]=1>ClCCl>[Cl:3][CH2:27][C:26]1[C:22]([C:16]2[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])=[N:23][O:24][C:25]=1[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Yield: 102.8 %

Procedure:
Thionyl chloride (87 mL, 1.20 mol) was added dropwise to a stirred solution of benzotriazole (143 g, 1.20 mol) in dichloromethane (400 mL) at room temperature. The resulting solution was added dropwise during 30 min to a stirred solution of [3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (263 g, 0.92 mol) in dichloromethane (700 mL). A very mild exothermic reaction occurred with precipitation of benzotriazole hydrochloride. The mixture was filtered to remove the benzotriazole hydrochloride. The filtrate was washed with water (2×800 mL), 1N sodium hydroxide (800 mL) and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated to give 288 g of the product as a pale yellow oil. 1H NMR (DMSO-d6): 7.66 (m, 2H), 7.61-7.57 (m, 1H), 4.47 (s, 2H), 3.45 (septet, J=7 Hz, 1H), 1.31 (d, J=7 Hz, 6H). ESI-LCMS m/z 279 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:42])[C:18]([OH:41])([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]=[C:28]([O:33]C(C)C)[CH:27]=[C:26]4[C:37]([F:40])([F:39])[F:38])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:43])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:42])[C:18]([OH:41])([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH:27]=[C:26]4[C:37]([F:38])([F:39])[F:40])[C:19]([F:20])([F:22])[F:21])=[C:13]([Cl:43])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(C(O)(C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)C(F)(F)F)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(c1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl)C(O)(c1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To 2-chloro-4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-2-(2-isopropoxy-4-trifluoromethyl-quinolin-6-yl)-1-methyl-propyl]-phenoxy}-benzonitrile (53 mg) was added acetic acid (270 mg) and aqueous HCl (37%, 92 mg). The mixture was stirred at 60° C. for 24 h. The mixture was neutralized with aqueous NaOH solution and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness to give the title compound (46 mg) as an orange solid. MS (m/e, ISP neg. ion)=599.1 [M−H+].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=3)=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C:3]([N:5]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6]1)=[O:4].[C:40]([C:44]1[S:48][C:47]([C:49](O)=[O:50])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].CN(C=O)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:40]([C:44]1[S:48][C:47]([C:49]([NH:1][C@@H:2]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:31]=4)=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[C:3]([N:5]2[CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:8]2)=[O:4])=[O:50])=[CH:46][CH:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
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: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution of (S)-methyl 1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (360 mg, 0.678 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (125 mg, 0.678 mmol) in DMF (6 mL, 77 mmol) was added DIEA (0.47 mL, 2.71 mmol) and the mixture cooled to 0° C. HATU (284 mg, 0.746 mmol) was added portion-wise and the reaction stirred at room temperature for 1 h. The mixture was poured onto citric acid (70 mL of a 10% w/w aqueous solution) and extracted with EA (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and solvents evaporated. Column chromatography (EA/iso-hexanes) gave 389 mg (82%) of (S)-methyl 1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as a pale yellow solid. LCMS-ESI (m/z) calculated for C40H48N4O5S: 696.3. found 697.0 [M+H]+, tR=3.60 min (Method 6).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Product: CCOC(=O)c1c[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A35) the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C[Al](C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:32]#[N:33])[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=1.C(Cl)Cl>C1(C)C=CC=CC=1.CO>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:32]([C:22]1[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=1)=[NH:33])([CH3:13])[CH3:12]
Reactant: COc1cc(C#N)cc(-c2ccccc2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To a 500 mL 3 neck flask, 2,6-diisopropylaniline (4.99 g, 27.3 mmol) and 100 mL toluene were charged. The mixture was cooled down in ice bath. Trimethylaluminum (20.48 mL, 41.0 mmol) was added dropwise via additional funnel. The reaction mixture was stirring at RT for 2 hours. Then, to the mix, added 5-methoxy-[1,1′-biphenyl]-3-carbonitrile (6.0 g, 28.7 mmol) dissolved in 50 mL toluene. The reaction mixture was heated to 70° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and poured it into silica gel mixed with DCM and methanol (2:1 ratio of DCM:methanol). The slurry was stirred and filtered and washed with DCM and methanol. The solvent was evaporated. The solid remaining after evaporation of solvent was added to 150 mL hexane and the mixture was stirred. The mixture was filtered and washed with hexane. After removal of solvent, 6.8 g of product was obtained for next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[CH2:19]=O>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][N:9]([CH3:19])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CNCC2c1ccccc1
Reactant: C=O
Agent: [Ni]
Solvent: CO
Product: COc1ccc2c(c1)CN(C)CC2c1ccccc1

Procedure:
(+)- 7 -methoxy- 4 -phenyl- 1,2,3,4 tetrahydroisoquinoline (2.4 g) was dissolved in methanol (50 ml) and 35% formaldehyde solution (3 ml) was added. The solution was stirred at ambient temperature for two hours when Raney nickel (1 g) was added and the solution hydrogenated at Atmospheric Pressure. The catalyst was removed by filtration, washed with ethanol and the filtrate and washings evaporated under reduced pressure to give the title compound as a colourless oil. Treatment of the title compound with ethereal hydrogen chloride gave its hydrochloride salt (2.3 g), m.p. 242° - 3° C. (dec) (methanol-ether) [α]D25 + 21.8° (water).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1(C)C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O-:30])=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22].[CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccc([N+](=O)[O-])cc1

Procedure:
Inversion of the configuration of the 17-position of oestradiol was achieved using a Misunobu reaction. The complex formed by triphenylphosphine and DEAD was reacted with the 3-O-benzyl-17-□-estradiol BLE99051 and p-nitrobenzoic acid at 80° C. in toluene to give the 3-O-benzyl-17-□-p-nitrobenzoate-estradiol BLE99053.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][C:14](=[O:29])[C:15]1[C:20](SC)=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=1OC)([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32](OC(=O)NC1CCCC1N)(C)C.C(C1C=C(C(F)(F)F)C=CC=1C(O)=O)C>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14](=[O:29])[C:15]1[CH:16]=[CH:17][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:20]=1[CH2:31][CH3:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Agent: CCc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C

Procedure:
The title compound, light yellow solid, MS: m/e=401.4 [(M+H)+], was prepared in accordance with the general method of intermediate N from [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) and 2-ethyl-4-(trifluoromethyl)-benzoic acid (CAS 854531-63-8).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](O)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20]1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH2:6][C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[O:16])[CH2:20]2)=[CH:31][CH:30]=1
Reactant: O=C(O)C1c2ccccc2Cc2ccccc21
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1c2ccccc2Cc2ccccc21

Procedure:
9,10-Dihydroanthracene-9-carboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-9,10-dihydroanthracene-9-carboxamide.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:32]=[C:31]([C:33]([CH3:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])[O:30][N:29]=4)=[O:26])=[CH:20][CH:19]=3)=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.Cl.[C:41](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=C(OC4CCNCC4)C=CN=3)=CC=2)C=1)(C)(C)[CH3:42]>>[CH2:41]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:32]=[C:31]([C:33]([CH3:39])([CH3:38])[C:34]([F:37])([F:35])[F:36])[O:30][N:29]=4)=[O:26])=[CH:22][CH:23]=3)=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1)[CH3:42]
Reactant: CC(C)(c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1)C(F)(F)F
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Agent: Cl
Product: CCN1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)cc3)nc2)CC1
Yield: 68 %

Procedure:
5-(1-Ethylpiperidin-4-yloxy)-N-(4-(3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)picolinamide (79 mg, 68%) was prepared using a procedure analogous to that described in Example 2, substituting 5-(piperidin-4-yloxy)-N-(4-(3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](C(O)=O)=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[N-:20]=[N+]=[N-].[Na+]>S(=O)(=O)(O)O>[NH2:20][C:7]1[C:6]([F:11])=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Temperature: 55 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (step-5 of Intermediate-51, 1.0 g, 3.48 mmol) in conc. sulphuric acid (10.0 mL) was added sodium azide (0.271 g, 4.18 mmol). The reaction mass was stirred at 50-60° C. for 18 h. The reaction mass was quenched in ammonia solution (cold) and solid obtained was filtered and suck dried to afford 0.570 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 4.21 (d, J=5.7 Hz, 2H), 5.30 (s, 2H), 6.39 (t, J=7.8 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 7.98 (m, 1H); MS (m/z): 259.12 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:11]=[N:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[CH3:4].CCN(S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:20]1([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]=2[CH:6]2[NH:5][C:3]([CH3:4])=[CH:2][O:1]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CO)NC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1=COC(c2c(-c3ccccc3)cnnc2-c2ccccc2)N1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of N-(1-hydroxy propan-2-yl)-3,5-diphenylpyridazine-4-carboxamide (150 mg, 0.45 mmol) in DCM (8 mL), DAST (145 mg, 0.90 mmol) was added at −78° C. and stirred for 2 h. After completion of starting materials, solid K2CO3 (248 mg, 1.80 mmol) was added to the reaction mixture at −78° C. and stirred at rt for 4 h. The reaction mixture was diluted with DCM (20 mL), washed with water (2×8 mL), saturated NaHCO3 (1×5 mL), water (1×5 mL), brine (1×2 mL) and dried over anhy. Na2SO4. Evaporation of the solvent under reduced pressure gave the crude product which was purified by column chromatography (100-200 mesh silica gel, 35% EtOAc-Hexane) to furnish 2-(3, 5-diphenylpyridazin-4-yl)-4-methyldihydrooxazole (compound 21) (90 mg, 63%) as pale yellow solid.