Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30]([N:36]3[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCNCCN1
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
1-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one was prepared from (4S,5R)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12d) and [1,4]diazepan-5-one (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 607.3 [(M+H)+]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:16])[C:14]#[CH:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:23][C:24]1([CH3:42])[C:36]2[CH:35]=[C:34](O)[C:33]3[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=3[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=2>>[C:17]1([C:13]2([C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:12][CH:11]=3)[O:16][C:34]3[C:33]4[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=4[C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([CH3:42])([CH3:23])[C:36]=4[C:35]=3[CH:15]=[CH:14]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)c2ccccc2-c2c1cc(O)c1ccccc21
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCOCC2)cc1
Product: CC1(C)c2ccccc2-c2c1c1c(c3ccccc23)OC(c2ccccc2)(c2ccc(N3CCOCC3)cc2)C=C1

Procedure:
The process for Step 3 of Example 1 was followed except that 1-(4-morpholinophenyl)-1-phenyl-2-propyn-1-ol (from Step 2) was used instead of 1-ferrocenyl-1-phenyl-2-propyn-1-ol to react with 7,7-dimethyl-7H-benzo[C]fluoren-5-ol to provide 3-phenyl-3-(4-morpholinophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran. Mass spectrometry analysis supported a molecular weight consistent with 3-phenyl-3-(4-morpholinophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[S:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42][CH2:43][C:44](O)=[O:45]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:44](=[O:45])[CH2:43][CH2:42][C:38]5[S:37][CH:41]=[CH:40][N:39]=5)[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: O=C(O)CCc1nccs1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: CC(OC(=O)CCc1nccs1)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 62 %

Procedure:
In analogy to Example 5, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using 3-(2-thiazolyl)propionic acid and, after workup and purification, 119 mg (62%) of the title compounds were obtained as a colourless foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
Indole-6-boronic acid (0.140 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (5-60% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.096 g in 79% yield.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccc(F)cc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C
Temperature: 110 °C
Yield: 89.3 %

Procedure:
To a dried 25 mL flask was introduced 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C, 110 mg, 0.48 mmol), methyl 2-bromo-4-fluorobenzoate (93.1 mg, 0.40 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), BINAP (24.9 mg, 0.04 mmol), and Cs2CO3 (182 mg, 0.56 mmol). The flask was degassed followed by the addition of toluene (1 mL), and the mixture was heated to 110° C. for 20 h. The mixture was then cooled to rt, and diluted with ethyl acetate. The solid was filtered off, and the solvent was removed under reduced pressure. The residue was redissolved in methanol/THF (4:1, v/v) and filtered through a C8-silica plug. HPLC purification using gradient elution from 30% to 90% acetonitrile in water afforded 136.2 mg (89%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.42 (s, 1H), 7.85 (dd, 1H), 7.21-7.30 (m, 4H), 6.86 (dd, 1H), 6.44 (dt, 1H), 6.11 (s, 1H), 3.70 (s, 3H), 2.04 (s, 3H), 1.30 (s, 9H). ES-MS m/z 381.9 (MH+); HPLC RT (min) 4.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:17])[CH:3]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14](=[O:16])[C:6]=2[CH:7]=1
Reactant: Cc1cc(Cl)ccc1-c1ccccc1C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1cc(Cl)cc2c1-c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
Under anhydrous calcium chloride drying conditions, a mixture of 4′-chloro-2′-methyl-biphenyl-2-carboxylic acid (21.60 g) and Eaton's reagent (7.7 w/w % solution of phosphorus pentoxide in methanesulfonic acid) (170 ml) was stirred at 100° C. for 2.5 hr. The reaction mixture was ice-cooled, water (500 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was mixed with 30 v/v % aqueous ethanol solution (200 ml), and the slurry was stirred at room temperature for 10 min, and filtered. The obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (19.744 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:10])=[C:4]([F:24])[CH:3]=1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]2[NH:30][C:31](=[O:33])[O:32][C:28]=2[CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:33]=[C:31]1[NH:30][C:29]2[CH:34]=[CH:35][C:26]([NH:25][C:21]([C:19]3[CH:18]=[CH:17][C:15]4[N:16]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:24])[S:13][C:14]=4[CH:20]=3)=[O:22])=[CH:27][C:28]=2[O:32]1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(Cc1ccc(Cl)cc1F)Nc1nc2ccc(C(=O)O)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1F)Nc1nc2ccc(C(=O)Nc3ccc4[nH]c(=O)oc4c3)cc2s1
Temperature: 25 °C
Yield: 20 %

Procedure:
Starting material 37 (60 mg, 0.2 mmol, 70% content) and 6-Amino-3H-benzooxazol-2-one (30, 25 mg, 0.2 mmol) were dissolved in 2 ml DMF. Then EDCI (38 mg, 0.2 mmol) and HOBt (31 mg, 0.2 mmol) were added. The reaction was stirred over night at ambient temperature, concentrated in vacuo and purified by prep HPLC (Method 1). By concentration of the pure fractions the desired product 38 (23 mg, 0.04 mmol, 24%) could be isolated.
Reaction SMILES: P(C[C:6]1[N:11]2C=C(C(O)=O)[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(O)(O)=O.[O:18]1CCC[CH2:19]1>>[NH2:14][C:10]1[N:11]=[CH:6][C:7]([CH2:19][OH:18])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cn2c(CP(=O)(O)O)cccc2n1
Product: Nc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 250 mL 3-neck flask equipped with an addition funnel, an argon (Ar) inlet and a stopper was flame dried and cooled to room temperature. Dry tetrahydrofuran (THF, 30 mL) was added to the flask, followed by 1M. lithium aluminum hydride (LAH) in Et2O (16 mL). After cooling the solution to 0° C. with a wet ice/water bath, the product from Example 8 (0.92 g, 6 mmol) suspended in THF (100 mL) was added dropwise. The reaction was allowed to warm to room temperature and stir for 3 h. The reaction was quenched with H2O, the salts filtered off and the filtrate stripped to give 0.591 g (99%) of title material.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1.Cl.S(Cl)([Cl:14])=O>C(Cl)Cl.O1CCOCC1.C1(C)C=CC=CC=1>[Cl:14][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cncc(CO)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1cncc(CCl)c1
Temperature: 60 °C
Yield: 70.8 %

Procedure:
To 0.2 g (1.49 mmol) of 5-(hydroxymethyl)pyridine-3-carbonitrile in 2 mL of DCM is added 1 mL (4 mmol) of HCl 4N in dioxane. The mixture is concentrated under reduced pressure and then added to 0.65 mL (8.95 mmol) of thionyl chloride followed by heating for 3 hours at 60° C. After cooling to room temperature, the medium is taken up in 20 mL of toluene, and the precipitate formed is filtered off and then treated with 30 mL of DCM and 30 mL of saturated NaHCO3 solution. The organic phase is separated out and dried over Na2SO4 and then concentrated under reduced pressure. 161 mg of 5-(chloromethyl)pyridine-3-carbonitrile are obtained in the form of an oil.
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[C:18]1([N:24]2[C:3]3[CH:4]=[CH:5][Se:1][C:2]=3[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccc[se]2)cc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 63 (5.86 g, 0.02 mole), phenylhydrazine 8 (4.36 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 66. Yield: 1.93 g (25.3%); white crystals;
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:27]3[CH2:28][CH2:29][CH:24]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:25][CH2:26]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nn2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(N3CCC(N4CCCCC4)CC3)nn2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-(piperid-1-yl)piperidine.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH3:15])[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH3:15])[CH:5]=1)=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ncsc2C)c1
Agent: [Li]
Product: Cc1scnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
A sample of 3-(5-methyl-thiazol-4-yl)-benzoic acid methyl ester (1.05 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(5-methyl-thiazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (1.9 g) as a pale-yellow oil.
Reaction SMILES: C1C([O:7]C2C=CC3C(OC(=O)C=3C=2)=O)=CC2C(OC(=O)C=2C=1)=O.[Cl-].[K+].[Cl-].C(N(CC)C(=[N+](CC)CC)N(CC)CC)C.[Cl:43][C:44]1[CH:54]=[CH:53][CH:52]=[C:46]2[C:47]([O:49][C:50](=[O:51])[C:45]=12)=[O:48].P(=O)(O)(O)O>O.ClC1C=CC=CC=1Cl>[Cl:43][C:44]1[CH:54]=[CH:53][CH:52]=[C:46]([C:47]([OH:7])=[O:48])[C:45]=1[C:50]([OH:49])=[O:51]
Reactant: O=C1OC(=O)c2cc(Oc3ccc4c(c3)C(=O)OC4=O)ccc21
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: CCN(CC)C(N(CC)CC)=[N+](CC)CC
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=C(O)c1cccc(Cl)c1C(=O)O

Procedure:
The purpose of this Example was to show that without decantation, a relatively higher level of impurities levels were present in the 4,4′-oxydiphthalic anhydride that was produced, as compared to Examples 4 and 5 where decantation is practiced. 2645 parts of a WC of material consisting of 68.7 wt % 4,4′-oxydiphthalic anhydride, 13.3 wt % of potassium chloride, 18 wt % of ortho-dichlorobenzene based on total weight of the WC, and some minor impurities such as hexaethylguanidinium chloride (1146 ppm) and chlorophthalic anhydride (1591 ppm), was mixed with 528 parts of phosphoric acid (85 wt %) and 11877 parts of water and heated under vacuum until boiling, about 80° C. Under these conditions, 4,4′-oxydiphthalic anhydride and chlorophthalic anhydride react with the water to form 4,4′-oxydiphthalic tetraacid (ODTA) and chlorophthalic acid (CIDA). The oDCB was removed from the mixture as an azeotrope with water. The weight of the reactor was maintained constant by adding the corresponding amount of water back to the reactor. The process took approximately 25 hours. Subsequently, the mixture was cooled to 14° C. and centrifuged. The WC was washed with 10 parts of water per part of 4,4′-oxydiphthalic tetraacid. 1492 parts of the final WC was obtained and it contained 85% of 4,4′-oxydiphthalic tetraacid and less than 30 ppm of hexaethylguanidinium chloride, 464 ppm of chlorophthalic acid and 64 ppm of potassium, with the balance (˜5 wt %) being water.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[C:22]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:23][CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.[OH-].[Na+].CCOC(C)=O.CN(C=O)C>[CH3:20][C:21]1[C:22]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][N:32]([C:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:13])[CH2:31][CH2:30]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2cccc3cccnc23)CC1
Temperature: 0 °C
Yield: 25.8 %

Procedure:
To a cold (0° C.), stirred, mixture of 8-quinoline carboxylic acid (177 mg, 1.02 mmol) in CH2Cl2 (10 mL) was added DMF (0.5 mL) followed by oxalyl chloride (0.45 mL, 5.16 mmol). The mixture was warmed to room temperature. After 20 minutes the mixture was concentrated under reduced pressure and provided a pink solid. To a solution of COMPOUND 249 (93 mg, 0.30 mmol) in THF (20 mL) was added the pink solid from above followed by DIPEA (1.10 mL, 6.31 mmol). The resultant mixture was stirred at room temperature for 2.5 hours then diluted with 1.0 N NaOH (20 mL) and EtOAc (60 mL). The phases were separated and the organic phase was washed with 1.0 N NaOH (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2-MeOH—NH4OH) provided 36 mg (26%) of COMPOUND 269 as a white foam. 1H NMR (CDCl3) δ 1.50-2.00 (m, 4H), 2.09 (s, 6H), 2.62-2.99 (m, 3H), 3.30-3.40 (m, 1H), 3.69-3.98 (m, 4H), 4.99-5.10 (m, 1H), 7.09 (dd, 2H, J=7.5, 4.8 Hz), 7.35-7.45 (m, 3H), 7.52-7.61 (m, 2H), 7.83-7.87 (m, 1H), 8.14-8.18 (m, 1H), 8.32 (d, 2H, J=3.9 Hz), 8.90-8.95 (m, 1H); ES-MS m/z 488 (M+Na).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:16]3[CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CO>>[NH2:29][CH2:28][CH2:27][CH:16]1[CH:15]([NH:14][C:10]2[N:9]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)[CH2:20][CH2:19][CH2:18][N:17]1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1
Agent: Cl
Solvent: CO
Product: NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1
Yield: 87 %

Procedure:
The compound 21 (102 mg) and 10% hydrogen chloride-methanol solution (2 mL) were stirred at room temperature for 5 hours. The reaction solution was concentrated, added aqueous 2N sodium hydroxide solution and then extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (71 mg) having the following physical properties.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[C:18](=[CH:1][N:2]([CH3:4])[CH3:3])[CH2:17]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 80 °C
Yield: 75.4 %

Procedure:
DMF dimethyl acetal (5.82 ml, 0.044 mol) was added to a stirred solution of 1-boc-4-piperidone [Ashwood et al., J. Chem. Soc., Perkin 1, 641 (1995)] (8.73 g, 0.044 mol) in DMF (80 ml) and the reaction mixture was heated to 80° C. under N2 for 18 h. After cooling, the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated to afford the subtitle compound as a solid (8.44 g, 76%). Rf 0.33 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 255 (MH+).
Reaction SMILES: [Br:1]/[C:2](/[CH:27]=C/C1C(C)(C)C2C(N=1)=[N+](CCCS([O-])(=O)=O)C=C(Cl)C=2)=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21]CS([O-])(=O)=O)[C:7]2[C:12]([C:13]\1([CH3:15])[CH3:14])=[CH:11][C:10](S([O-])(=O)=O)=[CH:9][CH:8]=2.[Na+:48].[Na+].[CH3:50][C:51]1([CH3:81])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:70])=[O:69])[CH:62]=[C:63]([S:64]([O-:67])(=[O:66])=[O:65])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]([CH2:72][CH2:73][CH:74]([S:76]([O-:79])(=[O:78])=[O:77])[CH3:75])=[C:52]1[CH3:80].[Na+].[Na+]>>[Br:1]/[C:2](=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH:74]([S:76]([O-:79])(=[O:77])=[O:78])[CH3:73])[C:7]2[CH:8]=[CH:9][C:10]3[C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:62][C:63]([S:64]([O-:67])(=[O:65])=[O:66])=[CH:57][C:11]=3[C:12]=2[C:13]\1([CH3:14])[CH3:15])/[CH:27]=[CH:80]/[C:52]1[C:51]([CH3:50])([CH3:81])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:69])=[O:70])[CH:62]=[C:63]([S:64]([O-:67])(=[O:65])=[O:66])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]=1[CH2:72][CH2:73][CH:74]([S:76]([O-:79])(=[O:77])=[O:78])[CH3:75].[Na+:48].[Na+:48].[Na+:48].[Na+:48].[Na+:48]
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Agent: [Na+]
Product: CC(CCN1/C(=C/C=C(Br)/C=C/C2=[N+](CCC(C)S(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)C(C)(C)c2c1ccc1c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc21)S(=O)(=O)[O-]

Procedure:
Compound 27 is prepared analogously to compound 9 (Example 9), except that compounds 24 and 26 is used as a starting material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(N1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20])(OC)=O.S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+].O>[CH:16]1[C:15](=[O:20])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:18](=[O:19])[CH:17]=1
Reactant: NCCCCCC(=O)O
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution of 4.2 g (32.3 mmol) of 6-aminocaproic acid in 163 ml of saturated sodium bicarbonate solution is treated at 0° C., with vigorous stirring, with 5 g (32.3 mmol) of N-carbomethoxymaleimide. After 1 hour, the solution is diluted with 256 ml of water and stirred at room temperature for 1 hour. The pH of the solution (8.2) is then brought to 6.4 by adding concentrated sulfuric acid. The solution is then concentrated to 100 ml and acidified to pH 2 by adding 1M sulfuric acid, and is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by chromatography on a silica column (elution: chloroform/acetic acid, 95:5). In this manner, 4.7 g of N-maleoyl-6-aminocaproic acid are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].C(O[C:14]([SH:16])=[S:15])C.[K]>CN(C=O)C>[SH:16][C:14]1[S:15][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=S)S
Reactant: N#Cc1ccc(Cl)c(N)c1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(S)nc2c1
Yield: 49 %

Procedure:
The title compound was prepared using the method of example 239, starting with 3-amino-4-chloro-benzonitrile (242) (9.0 g, 59.0 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 21.23 g, 132.7 mmol) in DMF (90 mL). 5.6 g (49%) of compound 243 was obtained as a pale brown solid.