Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]2[CH:19]=[N:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1.[OH:23][C:24]([CH3:39])([CH3:38])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[O:36][CH3:37].Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]2[CH:19]=[N:18][N:17]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:24]([OH:23])([CH3:39])[CH3:38])=[C:28]([O:36][CH3:37])[CH:29]=3)[C:16](=[O:20])[CH:15]=2)=[CH:21][CH:22]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1cc(COc2ccc(Cl)cc2)cn[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-n2ncc(COc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O

Procedure:
Pyridine (0.123 mL, 1.52 mmol) was added in portions over 4 hr to a stirred mixture of 5-((4-chlorophenoxy)methyl)pyridazin-3(2H)-one Part B (36 mg, 0.15 mmol), copper(II) acetate (91 mg, 0.46 mmol), and 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (73.0 mg, 0.30 mmol) in CH2Cl2 (15 mL) at RT (flask left open to air). The mixture was poured into 3.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (C18 column/H2O:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) giving the title compound 5-((4-chlorophenoxy)methyl)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one E-2 (25 mg, 38% yield) as an off-white solid. LC/MS 431 (M+H)+, tR 0.93 min (method 5); 1H NMR (500 MHz, Chloroform-D) δ ppm 7.94 (1H, d, J=1.92 Hz), 7.30 (2H, d), 7.12-7.17 (2H, m), 7.09 (1H, br. s.), 6.98 (1H, d, J=8.25 Hz), 6.91 (2H, d), 4.97 (2H, s), 3.82-3.92 (5H, m), 1.35 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1ccccc1N
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: COc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 23.4 %

Procedure:
Using the procedure of example 1, o-anisidine (100 mg) was reacted with compound 1f (100 mg) to provide compound 7 (20 mg, 24%). 1H NMR (400 MHz, CD3OD) δ 8.81 (d, J=8.0 Hz, 1H), 8.40 (m, 1H), 8.33 (d, J=4.8 Hz, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 7.23 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 7.08-7.01 (m, 3H), 3.97 (s, 3H). MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:21]2[C:12](=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][C@@H:15]([CH2:22][OH:23])[O:14]3)[CH2:11][CH2:10][CH:9]1O)=O)(C)(C)C>ClC1C=CC=CC=1Cl>[N:8]1[C:21]2[C:12](=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][C@@H:15]([CH2:22][OH:23])[O:14]3)[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1c2ccc3c(c2CCC1O)O[C@H](CO)CC3
Solvent: Clc1ccccc1Cl
Product: OC[C@@H]1CCc2ccc3ncccc3c2O1
Yield: 69.7 %

Procedure:
A solution of (6S)-2-hydroxy-6-hydroxymethyl-3,4,7,8-tetrahydro-2H,6H-5-oxa-1-aza-phenanthrene-1-carboxylic acid tert-butyl ester (0.33 mg, 1.0 mmole) in o-dichlorobenzene (15 mL) was stirred at 180° C. for 4 hours. The solvent was removed in vacuum. The residue was purified by column chromatography on silica gel (50% methylene chloride/hexane) to afford 0.15 g (71%) of the title compound as a solid, mp 128° C., [α]25D=+74.19° (c=7.7, DMSO).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:37])[NH:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:38]([CH:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]4)[N:39]=[CH:40][C:10]=13)[CH2:2]2>C(Cl)Cl.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:23][CH:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[O:37])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:38]([CH:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]4)[N:39]=[CH:40][C:10]=13)[CH2:2]2
Reactant: CCOC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NC5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NC5CCNCC5)cc4)nc32)CC1
Yield: 88 %

Procedure:
A solution of tert-butyl 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(ethoxycarbonyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ureido)piperidine-1-carboxylate (0.054 mmol) in CH2Cl2 (1 mL) and trifluoroacetic acid (0.2 mL) is stirred at room temperature for 2 hours, diluted with saturated sodium bicarbonate, extracted with CH2Cl2, washed with brine, dried and concentrated. Purification by HPLC provides ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-piperidin-4-ylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (88%). (HRMS=604.3356 (M+H, obs.), 604.3354 (M+H, calc.))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[Cl:20])(=[O:30])=[O:29])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1Cl
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
To a round-bottom flask, was added 5-bromo-2-chloropyridin-3-amine (0.2 g, 1.0 mmol, Asymchem Laboratories, Morrisville, N.C.) in THF (10 mL). To this solution, sodium bis(trimethylsilyl)amide (1M in THF, 3 mL, 3 mmol, Aldrich, St. Louis, Mo.) was added and the mixture was stirred for 5 minutes. Then 2-chloro-4-fluorobenzene-1-sulfonyl chloride (0.7 g, 3 mmol, Aldrich, St. Louis, Mo.) was added to the mixture and the suspension was stirred at 25° C. for 15 h. The mixture was diluted with H2O. The organic layer was collected by extracting the water with DCM (3×). The combined organic was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (1 to 30% EtOAc/CH2Cl2) gave N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-4-fluorobenzenesulfonamide (0.190 g, 49% yield) as a tan oil. MS (ESI positive ion) m/z: 401 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N:13]1[C:20](Cl)=[N:19][C:17](Cl)=[N:16][C:14]=1Cl.Cl>C1(C)C(C)=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][N:13]2[CH2:20][N:19]([NH:1][C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:17][N:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)[CH2:14]2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(NN2CN(Nc3ccc(C(=O)OCC)cc3)CN(Nc3ccc(C(=O)OCC)cc3)C2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
82.6 g of ethyl p-aminobenzoate and 30.75 g of cyanuric chloride in 1,500 ml of xylene were refluxed for 8 hours, hydrogen chloride escaping during this procedure. Thereafter, 1 liter of xylene was added, and the suspension, at 80°-90° C., was washed neutral with saturated sodium bicarbonate solution and then cooled to room temperature, and the product was filtered off over a glass suction filter. The white crystals obtained were washed with ethanol and dried. Mp: 218°-223° C.; yield: 97% of 1,3,5-tris-(p-ethoxycarbonylanilino)-s-triazine; ultraviolet (in ethanol): E1 cm1% =2,080 at 313 nm, E1 cm1% =699 at 218 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[C:12](=S)=[S:13]>CCO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:12](=[S:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2cc(Cl)ccc2o1
Reaction time: 7 h
Yield: 89 %

Procedure:
2-Amino-4-chlorophenol (5.0 g, 35 mmol) and potassium hydroxide (2.34 g, 41.8 mmol) were dissolved in carbon disulfide (50 mL) and EtOH (75 mL), and the reaction mixture was heated to reflux. After 7 h, the reaction mixture was concentrated under reduced pressure. The material was taken up in EtOAc (100 mL) and 1M HCl (50 mL). The aqueous layer was separated, and the organic layer was washed with water (50 mL) and brine (50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 5.71 g (89%) of the desired product as a brown solid. LC-MS: RT=7.60 min., [M+H]+=186.1.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:25])=O>C1(C)C=CC=CC=1>[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([Cl:25])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 5-phenyl-oxazole-4-carboxylic acid (67 mg, 0.35 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.91 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (co-evaporation with toluene) to give 5-phenyl-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[N:19][C:20]([O:23][CH2:24][CH3:25])=[N:21][CH:22]=1>O1CCCC1>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH3:25])=[N:21][CH:22]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOc1ncc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCOc1ncc(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cn1

Procedure:
4-[tert-Butyl(dimethyl)silyl]oxyaniline (1.8 g, 8 mmol) and 5-bromo-2-ethoxy-pyrimidine (1.6 g, 8 mmol) dissolved in anhydrous tetrahydrofuran (30 mL) are stirred for 1 hour at ambient temperature in the presence of sodium tert-butylate (4 mL, 2M solution in THF) and chloro(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)-phenyl]palladium(II) (111 mg, 0.16 mmol). The reaction mixture is filtered over Celite and then evaporated to dryness. The residue is triturated in heptane to obtain the expected compound after filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.1 g, 0.30 mmol) in methylene chloride (5 mL) was added 4-fluoro benzyl amine (0.04 g, 0.33 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.146 g, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.60 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (83 mg, 62% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.14 (d, J=4.0 Hz, 1H), 6.92-7.07 (m, 6H), 6.72 (d, J=4.0 Hz, 1H), 6.06 (bs, 1H), 4.58 (d, J=4.0 Hz, 2H), 4.34 (t, J=8.0 Hz, 2H), 3.16 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=439.1; Rt=1.55 min; HRMS (M+H)+=439.14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[C:11](=[NH:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH3:31]N>C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[C:11]([NH:29][CH3:31])=[N:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(=N)NC(=O)N2c1cccc(F)c1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(C(=O)OCc1ccccc1)[C@@H](C)C2
Reaction time: 8 h

Procedure:
To a flask containing benzyl (5R,7S)-4-amino-1-(3-fluorophenyl)-7-methyl-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (343 mg, 0.86 mmol; Intermediate 11-6) was added methylamine (2.0 M THF, 4.3 mL, 8.6 mmol). The vessel was sealed and placed in a 70° C. oil bath and stirred overnight. The reaction was diluted with aqueous NaHCO3 and extracted with EtOAc (three times). The combined organic layers were washed with brine, isolated and subsequently dried over Na2SO4. Evaporation of solvent and further drying under vacuum gave crude product that was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (26.00 mg; 0.15 mmol; 1.00 eq.) in DMF were added bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (35.01 mg; 0.14 mmol; 0.90 eq.), 4-{[1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (41.33 mg; 0.13 mmol; 0.88 eq.), and N-ethyl-N-isopropylpropan-2-amine (0.07 ml; 0.38 mmol; 2.50 eq.). The reaction mixture was stirred overnight at RT. Purified the crude by HPLC to obtain 20 mg of the title product in 28% yield. MS (M+1) 460
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH2:19]([NH2:22])[C:20]#[CH:21]>>[CH2:19]([NH:22][C:13]([C:11]1[S:12][C:8]([C:5]2[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15])[C:20]#[CH:21]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C#CCN
Product: C#CCNC(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and propargylamine by the method described in Example 2 Method B. Pale yellow solid (122 mg, 97%). 1H NMR (DMSO-d6) 2.41 (d, J=1.3, 3H), 3.25 (t, J=2.6, 1H), 4.13 (dd, J=5.7, 2.6, 2H), 7.79 (d, J=4.0, 1H), 7.97 (d, J=4.0, 1H), 9.29 (t, J=5.7, 1H). 19F NMR −62.30. LC/MS 6.07 min, [M+1]+ 315.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D118) (24 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D86) (40 mg) and 4-(trifluoromethyl)benzylbromide (0.032 ml). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30]C5C(C)=NC=CC=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:38][C:39]1[CH:44]=[C:43](O)[CH:42]=[C:41]([CH3:46])[N:40]=1>>[CH3:38][C:39]1[CH:44]=[C:43]([O:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]3[N:21]=[N:20][N:19]([CH:10]4[CH2:9][CH2:8][C:7]5[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=5[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:11]4=[O:18])[CH:23]=3)=[CH:25][CH:26]=2)[CH:42]=[C:41]([CH3:46])[N:40]=1
Reactant: Cc1cc(O)cc(C)n1
Reactant: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1
Product: Cc1cc(Oc2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)cc(C)n1

Procedure:
Prepared as for 6-fluoro-3-(4-{4-[(2-methylpyridin-3-yl)oxy]phenyl}-1H-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 2,6-dimethyl-4-hydroxypyridine.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH:17]2[CH2:19][CH2:18]2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21].NN>C(O)C.CCCCCCC.Cl>[CH:17]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:6]=2[C:4](=[O:5])[N:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)[N:21]=3)[CH2:18][CH2:19]1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Agent: Cl
Agent: NN
Solvent: CCCCCCC
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Yield: 80.2 %

Procedure:
4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 0.0041 mols) and 4-hydrazino-benzoic acid (1.0 g, 0.0068 mols) were stirred in ethanol (30 ml) at reflux for 16 h. The bright yellow suspension was diluted with heptane, filtered, washed with cold t-butylmethyl ether and left to dry under suction to yield crude solid containing hydrazine. This solid was suspended in 1 M HCl, filtered, washed with water and then dried in vacuo to yield 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (1.135 g, 80%) as a yellow solid, LCMS m/z 346.20 [M+H]+ @ RT 1.05 min: 96% purity. δH (400 MHz, (CD3)2SO) 11.4 (1H, s), 8.43 (2H, d, J 8.1), 8.21 (1H, dd, J1 1.2, J2 8.1), 8.07 (2H, d, J 8.1), 7.92 (1H, d, J 8.1), 7.67 (1H, t, J 6.6), 7.52 (1H, t, J 6.5), 3.43 (1H, m), 1.59 (2H, m), 1.43 (2H, m). Step 4 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]-quinolin-2-yl)-benzoyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:31])=[C:16]([C@@:18]2([CH3:30])[N:26]=[C:25]([NH2:27])[C:21]3([CH2:24][CH2:23][CH2:22]3)[S:20](=[O:29])(=[O:28])[CH2:19]2)[CH:17]=1>>[NH2:27][C:25]1[C:21]2([CH2:24][CH2:23][CH2:22]2)[S:20](=[O:28])(=[O:29])[CH2:19][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:13]=[CH:14][C:15]=2[F:31])([CH3:30])[N:26]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Yield: 50324.7 %

Procedure:
Prepared from 5-chloropicolinic acid (48.6 mg, 308 μmol, Eq: 1.2) and (R)-7-(5-amino-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (80 mg, 257 mmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (70 mg, 155 mmol, 60.4% yield) as a light yellow foam. MS (ISP): m/z=451.4 [(M+H)+] and 453.2 [(M+2+H)+].
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([O:24]C(C2OC=CC=2)=O)([C:20]([CH2:22][Cl:23])=[O:21])[C@:18]2([CH3:32])[C@H:4]([C@H:5]3[C@:15]([Cl:34])([C@@H:16]([OH:33])[CH2:17]2)[C@:14]2([CH3:35])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[Na+].[Cl-]>O>[CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][Cl:23])=[O:21])[C@:18]2([CH3:32])[C@H:4]([C@H:5]3[C@:15]([Cl:34])([C@@H:16]([OH:33])[CH2:17]2)[C@:14]2([CH3:35])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A sample of the complexed mometasone furoate monohydrate stock suspension (4 g) was mixed with an appropriate diluent (27.2 g) (deionized water or saline (0.9% NaCl/deionized water (w/w)) and mixed thoroughly to obtain the 0.05% w/w mometasone formulations containing 0.097% HPMC, 0.002% sodium lauryl sulfate, 0.014% methylparaben sodium, 0.016% citric acid anhydrous, 0.009% potassium sorbate and approximately 0.5 ppm of 30% simethicone emulsion.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH:23]([C@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][CH2:33][CH2:34][C:35]1[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[CH:37][CH:36]=1)=O>C1COCC1>[O:31]=[S:27]1(=[O:30])[CH2:28][CH2:29][C@H:25](/[CH:23]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:26]1[CH2:32][CH2:33][CH2:34][C:35]1[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(CCCN2[C@@H](C=O)CCS2(=O)=O)s1
Reactant: COP(=O)(CC(=O)Cc1cccc(C(F)(F)F)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2[C@@H](/C=C/C(=O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a suspension of sodium hydride (12 mg, 0.5 mmol) in THF (1.0 mL) cooled to 0° C. was added a solution of dimethyl (2-oxo-3-(3-(trifluoromethyl)phenyl)propyl)-phosphonate (160 mg, 0.52 mmol) in THF (2.0 mL). After 15 min a solution of the aldehyde 11 (155 mg, 0.47 mmol) in THF (2.0 mL) was added. The reaction was allowed to warm room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 40% EtOAc/hex) afforded 240 mg (99%) of enone 12.