Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1cccc(N=C=O)c1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.9 mg (0.21 mmol) of 3-methoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 17 mg (32.7% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[CH:3]=1.N1C=CC=CC=1.S(OC)(O[C:24](SC)([S:27][CH3:28])[S:25][CH3:26])(=O)=O>O1CCOCC1>[CH3:26][S:25][C:24]([S:27][CH3:28])=[C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]1=[O:13]
Reactant: CC(C)CCn1ccc(O)cc1=O
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
The product of Example 457B (2.24 g, 12.37 mmol) in pyridine (8.0 mL, 98.96 mmol) and dioxane (50 mL) at 90° C. was treated with excess tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi), stirred at 90° C. for 1.5 hours and cooled to about 25° C. The reaction solution was decanted from the resulting solids and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and loaded onto a pad of silica gel (300 mL) and eluted with hexane followed by dichloromethane then 25% ethyl acetate in dichloromethane to provide the title compound (2.42 g, 75%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[C:29]#[C:30][CH3:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[C:29]#[C:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC#CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC#CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (93 mg, 94%), MS (ISP) m/z=397.4 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and but-2-ynoic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 7-(2-phenyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (1.07 g, 2.338 mmol) in THF (12 ml) and water (6 ml) was treated with LiOH (0.560 g, 23.38 mmol) and stirred at 70° C. for 18 hours. After cooling to RT, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 ml) and the pH was adjusted to pH˜4 using 2M HCl. The aqueous portion was extracted with EtOAc (2×20 ml). The organic extracts were washed with brine, dried (MgSO4) and evaporated under vacuum. The residue was dissolved in hot (˜80° C.) ethanol (20 ml) and water (˜15 ml) was added until the solution became turbid. Upon cooling a solid precipitated. The mixture was kept cold for 72 hours.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:37]4[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=4)[C:31]#[N:32])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(CC3CCCCC3)C2=O)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.064 mmol) in 1,4-dioxane (1.5 mL), Cs2CO3 (2 N, 0.5 mL) and 3-cyanophenylboronic acid (19 mg, 0.128 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-(cyclohexylmethyl)-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (9.74 mg, 31%). 1H-NMR (MeOD): 1.02 (m, 5H), 1.62 (m, 6H), 2.03 (m, 1H), 2.24 (m, 1H), 3.30 (m, 1H), 3.44 (m, 1H), 5.91 (m, 1H), 6.97 (m, 1H), 7.16 (m, 1H), 7.25 (m, 1H), 7.35 (m, 3H), 7.46 (m, 2H), 7.56 (m, 1H), 7.71 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[C:6]([OH:8])[CH:7]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[Cl:22][CH:23]([C:27](=O)[CH3:28])[C:24](=O)[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:27]([CH3:28])=[C:23]([Cl:22])[C:24]([CH3:25])=[N:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NNc1ccc(Br)cc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1nn(-c2ccc(Br)cc2O)c(C)c1Cl
Yield: 76.9 %

Procedure:
558 mg of the title compound was prepared in a manner similar to Example 54b) by using 5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate (0.9 g), which was prepared in a manner similar to Example 54a), and 3-chloropentane-2,4-dione (1.07 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[C:4]([CH3:19])([CH3:18])[C:3]1=[O:20].[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[C:4]([CH3:18])([CH3:19])[C:3]1=[O:20]
Reactant: CCOC(=O)/C=C/c1cccc2c1N(C)C(=O)C2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)C(C)(C)c2cccc(/C=C/C(=O)O)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (2E)-3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)acrylate (25 mg, 0.091 mmol) in MeOH (1 mL) was added 1 N aqueous NaOH (0.1 mL) and the resulting mixture was stirred at ambient temperature for 18 h. To the reaction mixture was added 1 N aqueous HCl (0.1 mL) and the resulting mixture was concentrated to dryness under reduced pressure to give the title compound. MS: m/z=246 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](CC#N)[CH:7]=1.[C:12]([OH:15])(=[O:14])[CH3:13].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:11])=[C:4]([CH2:13][C:12]([OH:15])=[O:14])[CH:3]=1
Reactant: CC(=O)O
Reactant: N#CCc1cc(Br)ccc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(Br)ccc1F

Procedure:
(5-Bromo-2-fluoro-phenyl)-acetonitrile (0.5 g, 2.3 mmol) was treated with acetic acid (2 mL) and sulfuric acid (2 mL) in H2O (2 mL) at 95° C. for 5 hours. Aqueous worked-up afforded the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([NH:37]C(C)(C)C)(=[O:36])=[O:35])=[CH:24][CH:23]=2)[C:8]2=[N:9][CH:10]=[C:11]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([NH2:37])(=[O:36])=[O:35])=[CH:26][CH:27]=2)[C:8]2=[N:9][CH:10]=[C:11]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Nc1cnc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(=O)Nc1cnc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 12 h

Procedure:
A solution of 2-butyl-3-[[2'-[[(1,1-dimethyl-ethyl)amino]sulfonyl][1,1'-biphenyl]-4-yl]methyl]-6-[(1-oxopentyl)amino]-3H-imidazo[4,5-b]pyridine (710 mg, 1.23 mmol) in trifluoroacetic acid (50 mL) was stirred at r. t. for 12 h. The mixture was concentrated, dissolved in EtOAc (40 mL) and washed with saturated aqueous Na2CO3. The organic extracts were dried (K2CO3) and concentrated to give the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=O)[CH:4]=1)#[N:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:24])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 81 %

Procedure:
Following a procedure similar to that described in Preparation 16a, but using 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described in Example 1(b)] and t-butylamine as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained in a yield of 81%.
Reaction SMILES: [F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl>ClCCl.CO.ClCCl>[F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCNCC1
Reaction time: 8 h
Yield: 111.5 %

Procedure:
1,1-Dimethylethyl 4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidine carboxylate (D2, 546 mg, 1.14 mmol) was dissolved in dichloromethane (10 mL) at rt. HCl (10 mL, 40 mmol, 4 M in 1,4-dioxane) was added and the reaction was stirred overnight. It was then concentrated by rotary evaporation to give a pale brown solid. The residue was dissolved in methanol/dichloromethane and purified by SCX (5 g, eluting with methanol, followed by 2 M ammonia in methanol). The ammonia/methanol fraction was concentrated by rotary evaporation to give 6-fluoro-5-methyl-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one (D3, 318 mg, 72% purity, 80% yield) as an orange oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].C(OCC)(=O)C>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCCC(=O)NCC(=O)O
Yield: 79.5 %

Procedure:
Glycine (20 mmol) was reacted with nonanoyl chloride (22 ml) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 1 Part A. The crude crystalline product (4.25 g) was recrytallized from ethyl acetate (40-50 ml) to give the title compound (3.42 g, 79.5%), m.p. 106°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH3:25][CH:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:28]([CH:26]([CH3:27])[CH3:25])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: Nc1ccsc1-c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 43985.1 %

Procedure:
Charge a double jacketed 20 L reactor equipped with mechanical stirrer and set under inert atmosphere of argon with 2-(4-Bromo-phenyl)-thiophene-3-ylamine (562 g, 2.21 mol) and CH2Cl2 (9.435 L). Obtain a clear solution. Add DBU (1.999 L) and cool the mixture to 9.4° C. Add propane-2-sulfonyl chloride (0.616 g) in 20 minutes maintaining the temperature below 25° C. Stir the reaction mixture 22 h at 20° C. After completion of reaction, cool the reaction mixture to 11° C. and add an aqueous solution of satd. aq. NH4Cl (7.65 L) cooled at 10° C. in 5 minutes. Heat the mixture to 20° C. and separate the aqueous phase. Wash the organic layer with 2N HCl (5.12 L), evaporate to dryness and take the residue into ethyl alcohol (800 g) . Heat the mixture until complete dissolution at 70° C. Cool the solution to 41° C. and add water (1384 mL). Stir the suspension overnight at 22° C., filter and wash two times with 254 mL of a 1/1 EtOH/H2O mixture. Dry the resulting beige solid under vacuum at 26° C. for 4 days to give propane-2-sulfonic acid[2-(4-bromo-phenyl)-thiophene-3-yl]-amide (688 g, 1.9 mol). 1H NMR (250 MHz, CDCl3): 1.25(d,6 H, J=6.9 H), 3.16 (hept, 1 H, J=6.9 Hz), 7.28(pseudo s, 2 H), 7.33(d, 2 H, J=8.5 Hz), 7.6(d, 2 H, J=8.5 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]([CH3:17])[C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:20]O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:18][N:20]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Yield: 3.6 %

Procedure:
The lithium enolate of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (1.5 g, 5.5 mmol) and hydroxylamine hydrochloride (0.46 g, 6.6 mmol) in absolute ethanol (30 mL) were heated to reflux for 17 hours, cooled to room temperature, then cooled to 0° C. for 3 hours. The resulting white crystals were collected and dried under vacuum to obtain ethyl 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylate (0.55 g, 0.20 mmol).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 mmol) in CH2Cl2 was added triethylsilane (67 μl, 0.42 mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to provide the title compound (45 mg, 31%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)C)c1OCC1CC1
Temperature: 70 °C
Yield: 21.4 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and isobutylbromide (101 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 21%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[CH3:37].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[CH3:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:15][N:16]=2)[CH2:21][CH2:22]1)[C:32]([OH:34])=[O:33]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5C)CC4)nc3)cc21

Procedure:
3-methyl-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-3-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H29N5O3 (m/e) 483, obsd 484 (M+H).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2CCN(C([C@@H](NC(=O)OC(C)(C)C)CC(C)C)=O)CC2)C=CC=CC=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:29][CH2:28]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CN2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Product: COc1ccc(CN2CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC2)cc1
Yield: 95.5 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (7.47 g) and 1-(4-methoxy-phenylmethyl)piperazine (6.18 g) were condensed in the same manner as employed in the preparation of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate to yield 12.0 g of tert-butyl (s)-1-[4-(4-methoxyphenylmethyl)piperazine-1-yl carbonyl]-3-methylbutylcarbamate as a colorless amorphous substance (yield: 95%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(SCCN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(SCCNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of compound 1-HCl (0.44 g) in CH2Cl2 (15 mL) cooled to ˜0° C. was added acetyl chloride (1.0 mL) and triethylamine (1.0 mL). The reaction mixture was stirred for 1 hour at 0° C. and washed with 1N HCl, sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 10 as solid (pure by TLC and NMR). Yield: 0.5 g.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][CH2:16][CH3:17])[C:7]=12.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][CH2:16][CH3:17])[C:7]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: CCC=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 75.9 %

Procedure:
The title compound (trans) was prepared as a white powder in 75.9% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-pentenyl)pyrrolo[2,3-d]pyridazine (trans) and benzyl alcohol.
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([C:25]#[CH:26])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1OS(C)(=O)=O)(=O)C.C1CN2C(=NCCC2)C1>CC#N>[C:25]([C@:6]1([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)#[CH:26]
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Reaction time: 12 h

Procedure:
A mixture of 13 (105 mg, 0.272 mmol) and DBN (101 μL, 0.815 mmol) in CH3CN (10 mL) was refluxed for 11 h. After being quenched with AcOH, the reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). The product, obtained after purification by silica gel column chromatography (hexane/EtOAc=1/1) of the organic layer, was dissolved in saturated NH3 in MeOH (30 mL), and kept at room temperature for 12 h. Evaporation of the solvent followed by preparative TLC (hexane/EtOAc=1/1) purification gave TKD-4-114 (49.6 mg, 74%) as a solid: mp 207-209° C.; UV (MeOH)λmax 264 nm (ε10800), λmin 235 nm (ε4800); 1H NMR(CDCl3)δ1.83 (3H, s, Me), 2.63 (1H, s, ethynyl), 3.47 (1H, br, OH), 3.88 (1H, d, Jgem=12.5 Hz, H-5′a), 3.96 (1H, d, Jgem=12.5 Hz, H-5′b), 5.91 (1H, dd, J1′,2′=1.1 Hz and J2′,3′=5.9 Hz, H-2′), 6.30 (1H, dd, J1′,3′=2.0 Hz and J2′,3′=5.9 Hz, H-3′), 7.16-7.17 (1H, m, H-1′), 7.44 (1H, d, J6,Me=1.1 Hz, H-6), 9.06 (1H, br, NH); FAB-MS m/z 249 (M++H). Anal. Calcd for C12H12N2O4.1/6H2O: C, 57.37; H, 4.95; N, 11.15. Found: C, 57.36; H, 4.69; N, 10.98.