Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1[C:24]2[CH:23]([NH2:25])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:25][CH:23]2[C:24]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][CH2:21][CH2:22]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NC1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1
Yield: 98 %

Procedure:
Using general procedure B: Reaction of Boc-4-piperidone (641 mg, 3.22 mmol 5,6,7,8-Tetrahydro-quinolin-8-ylamine (476 mg, 3.22 mmol), sodium triacetoxyborohydride (1.36 g, 6.44 mmol) and acetic acid (0.25 mL) in THF (25 mL) at room temperature under N2 for 20 min afforded the title compound (1.05 g, 98%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]2[CH:16]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[NH:9][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc3c(O)nc(N)nc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A solution of 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1 g, 7.93 mmol) and sodium acetate (0.85 g, 10.32 mmol) in water (180 mL) was stirred at 100° C. for 30 minutes. Methyl 4-(2-bromoacetyl)benzoate (2.24 g, 8.72 mmol) was suspended in MeOH (25 mL) and was added slowly to the above solution. The reaction mixture was then stirred at 100° C. for 16-20 h and then cooled to room temperature. The residue was filtered and dried. It was then stirred in CH2Cl2 (10 mL) and filtered to provide XI-8-I (1.07 g, 47.5%). LCMS: m/z 285 (M+1)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (573 mg, 2.60 mmol) was treated with 4-methoxyaniline (800 mg, 6.5 mmol) using method A to give 4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid as an off white solid. Yield: 528 mg (66%). 1H-NMR: 10.05 (s, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 3.67 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N(C1C=C(S(N)(=O)=O)C=CC=1)=[C:13]=[O:14]>>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[C:13]=[O:14]
Reactant: NS(=O)(=O)c1cccc(N=C=O)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=C=O)cc1

Procedure:
This compound is prepared from 4-aminobenzenesulphonamide using a procedure analogous to that of 3-isocyanato-benzenesulfonamide (Intermediate ED) by replacing 3-aminobenzene-sulphonamide with 4-aminobenzenesulphonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=1>CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])[CH:21]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 53.8 %

Procedure:
To a solution of 150 mg of 3-(4-fluorophenyl)-1H-5-indazolecarboxylic acid produced in Production Example I-14 in 2.5 ml dimethylformamide were added a solution of 70 mg of 3-picolylamine in 0.5 ml dimethylformamide and 124 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (═WSC.HCl), and the mixture was stirred at room temperature for four days. After removing the solvent by distillation, the residue was dissolved in 25 ml of ethyl acetate. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether, to give 109 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[C:10](=[O:11])[NH:9][N:8]([CH3:12])[C:7]2=[N:13][C:14]([NH2:18])=[N:15][C:16](=[O:17])[C:6]=12)C(C)=O>COCCO>[NH2:18][C:14]1[NH:15][C:16](=[O:17])[C:6]2[CH:5]([CH3:1])[C:10](=[O:11])[NH:9][N:8]([CH3:12])[C:7]=2[N:13]=1
Reactant: CC(=O)Cc1c2c(=O)nc(N)nc-2n(C)[nH]c1=O
Solvent: COCCO
Product: CC1C(=O)NN(C)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
4-Acetonyl-7-amino-1-methylpyrimido{4,5-c}-pyridazine-3,5-(1H, 2H)-dione (0.054 g) was dissolved in boiling methyl cellosolve (1 l), and the solution was concentrated to 40 ml when precipitated solid was noticed to be present. The mixture was allowed to cool to room temperature and stand overnight. Yellowish-green solid was collected, washed with methyl cellosolve (10 ml) methanol (2 ml), and dried under vacuum at 75° C. to yield 0.018 g (35%) of product: nmr (CF3COOH) δ 3.03(s, 3H), 4.26(s, 3H), 6.83(br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13]C)=[O:12].P(=O)(O)(O)O>[OH-].[K+]>[CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2scnc2c1C
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1c(C(=O)O)ccc2scnc12

Procedure:
16.6 g of methyl 4-methylbenzothiazole-5-carboxylate (0.08 mol) were dissolved in 280 ml of 5% strength aqueous potassium hydroxide solution and heated at reflux for 2.5 h. After cooling, the mixture was acidified using phosphoric acid. The product was filtered off and subsequently dried.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:6].Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:6]
Reactant: COc1ccccc1C(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4ccccc4O)cccc32)cc1
Temperature: 180 °C
Yield: 96 %

Procedure:
A mixture of 85 g of the product of Step B and 600 g of pyridine hydrochloride was heated at 180° C. for 4 hours and the mixture was cooled to 80° C. 700 ml of a saturated solution of sodium carbonate were added followed by extraction with ethyl acetate. The extracts were washed twice with 300 ml of N hydrochloric acid and then with water, dried and evaporated to dryness under reduced pressure. The 100.3 g of residue were chromatographed on silica (eluant: methylene chloride - hexane (8-2)) to obtain 78.8 g of the expected product which was used as is for the following step and melted at 110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40]O)=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:47]#[CH:48])(C)C.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:47]#[CH:48])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2Oc2ccc(OCCO)cc2)N1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Oc2ccc(OCC)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in Example 2, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.9 g, 1.26 mmol) was reacted with trimethylsilyl acetylene (0.25 g, 2.5 mmol), CuI (0.48 g, 2.5 mmol), triethylamine (0.25 g, 2.5 mmol) and dichlorobis(triphenylphosphine) palladium(0) (0.18 g, 0.025 mmol) in tetrahydrofuran, then treated with aqueous NaOH solution in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{5-ethynyl-2-[4-(2-ethoxy)-phenoxy]-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.58 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.Br[CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:9][CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)c1cccnc1
Reactant: COC(=O)C(Br)CC(C)C
Product: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1cccnc1

Procedure:
Using the same protocol as described in example 23, step 2, (4-bromophenyl)(pyridin-3-yl)methanol from step 1 (644 mg, 2.4 mmol) was added to methyl 2-bromo-4-methylpentanoate (412 μL, 2.52 mmol). The crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCCCC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and piperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.28 (d, 1H), 8.22 (m, 1H), 7.88 (m, 1H), 7.59 (m, 2H), 7.42 (d, 1H), 7.40 (s, 1H), 7.15 (m, 1H), 7.05 (d, 1H), 4.35 (broad t, 2H), 3.61 (m, 4H), 3.38 (s, 4H), 2.90 (broad t, 2H), 2.60 (m, 4H), 1.60 (m, 6H). MS: 461.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCCOC1CCCCO1
Product: CCOC(CNCCOC1CCCCO1)OCC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran (3.03 ml, 20 mmol) and the obtained residue was purified by Bach silica gel column chromatography (eluent: chloroform:methanol=100:0 to 98:2) to obtain the title compound (1.59 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1I.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]2[CH:31]=[C:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:4]=2[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(I)c2O)c1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(-c4ccccc4)oc23)c1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 23.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 1.5 grams (0.003 mole) of 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.41 gram (0.004 mole) of phenylacetylene, and 0.71 gram (0.007 mole) of triethylamine in 25 mL of DMF was stirred. To this was added 0.09 gram (0.00013 mole) of dichlorobis(triphenylphosphine)pallidium (II) and 0.05 gram (0.00026 mole) of copper (I) iodide. Upon completion of addition, the reaction mixture was heated to 70° C. where it stirred for 2.5 hours. After this time, the reaction mixture was cooled to ambient temperature and then poured into 150 mL of an aqueous 10% ammonium chloride solution. The resulting precipitate was collected by filtration and washed with water. The precipitate was taken up in 120 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a brown solid. The solid was recrystallized using 1:1 chloroform and petroleum ether, yielding 0.31 gram of Compound 280. The mother liquor was concentrated to a residue. The residue was recrystallized using petroleum ether to yield an additional 0.21 gram of Compound 280, m.p. 215-216° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][CH:6]=[C:5]3[O:4][C:3]2[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cc(C(F)(F)F)ccc4F)ccnc23)c1F
Yield: 43.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-35, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 133 mg, 0.46 mmol), oxalyl chloride (187 mg, 0.69 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) in CH2Cl2 (4 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.78 (d, J=7.8 Hz, 1H), 8.70 (d, J=5.4 Hz, 1H), 8.11-8.05 (m, 3H), 7.83-7.71 (m, 3H), 7.41-7.30 (m, 2H), 6.83 (d, J=4.8 Hz, 1H), 4.29 (d, J=5.4 Hz, 2H), 1.12 (s, 9H); MS (m/z): 592.33 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](OCC#CC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 51.1 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy)pregna-5,7,16-triene (74.1 mg, 0.0963 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a pale yellow oil (21.0 mg, 51%).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][N:40]([C:47](=O)[CH2:48]Cl)[CH2:39]2>>[CH:38]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][N:40]([CH2:47][CH2:48][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=1)[CH2:39]2
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CC4CCC(CC4)C3)cc2)c1
Yield: 11.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.7 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: CC(C)CBr
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 80 °C
Yield: 42.7 %

Procedure:
6-Bromo-5-(2,4-difluorophenoxy)-1H-indazole (60.0 g, 185 mmol) was dissolved in DMF and treated with K2CO3 (76.5 g, 554 mmol) and isobutyl bromide (126.4 g, 923 mmol). The reaction mixture was stirred and heated to 80° C. for 16 hours. An additional 15 g of K2CO3 were added and the mixture was vigorously stirred for an additional 24 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and dissolved in ether (1 L). The ether layer was washed with 1:5 brine/water (2×600 mL). The aqueous phases were extracted with ether (300 mL) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was chromatographed on a Biotage Flash 75 in two batches (about 35 g each) eluting with 5% ethyl acetate in hexanes. The combined purified products yielded 30.1 g of the desired product as a solid (43% yield). MS (ESI+) m/z 381, 383 (M+1, Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.72 (s, 1H), 7.16 (s, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 4.12 (d, 2H), 2.34 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=O.[CH:14]([NH2:16])=O>CC(C)=O>[O:13]=[C:11]1[C:3]2[C:2](=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[N:1]=[CH:14][NH:16]1
Reactant: NC=O
Reactant: Nc1ccc(C(=O)O)cc1C(=O)O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2nc[nH]c(=O)c2c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
A mixture of 4-amino isophthalic acid (17 g, 0.093 mol) and formamide (85 mL) was heated at 180° C. for 5 h. The reaction mixture was cooled to RT and added acetone. The solid precipitate thus obtained was stirred for 2 h, filtered and dried to give 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (11 g, 61%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[CH:30]=4)[CH:24]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M6) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (68 mg).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Cl.[OH-].[Na+]>CN(C=O)C.C(O)C>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:30])([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]([OH:31])=[O:3])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccccc1CN1CC(CCOc2ccc(CC(C)(Oc3ccccc3)C(=O)O)cc2)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.12 g, 0.281 mmol) in DMF (7 mL) is treated with NaH (60% oil suspension, 0.023 g, 0.575 mmol) and stirred at room temperature under N2 for 20 minutes. The reaction is treated with 2-methoxybenzyl chloride (0.066 g, 0.421 mmol) and then warmed to room temperature and stirred for 3 h. The reaction is quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer is dried (MgSO4) and the solvent removed in vacuo to afford crude product that is dissolved in ethanol (20 mL) is treated with aqueous 5 N NaOH (1.5 mL) and heated to ref lux 1 h. The reaction mixture is cooled, the solvent removed in vacuo. The resultant residue is acidified with aqueous 1 N HCl (20 mL) and extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to afford crude acid that is purified by preparative HPLC to give 0.077 g (53%) of 3-(4-{2-[1-(2-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid. 1H NMR. HRMS (ES+) m/z exact mass calc'd for C30H35N2O6 (M+1) 519.2495. Found m/z 519.2515.