Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[OH:9][C@H:10]1[CH2:14][NH:13][CH2:12][C@@H:11]1[CH2:15][OH:16].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][C@H:10]([OH:9])[C@@H:11]([CH2:15][OH:16])[CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC[C@H]1CNC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reaction time: 1 h

Procedure:
Sodium hydroxide (2.70 g) was dissolved in water (25 mL) and dioxane (15 mL) was added to the solution. (3R,4R)-(4-Hydroxypyrrolidin-3-yl)methanol (1.00 g) was then dissolved in the solution. While the mixture was chilled in an ice water bath, carbobenzoxy chloride (0.97 mL) was added dropwise. The reaction mixture was stirred at 5° C. or below for 1 hour and a second portion of carbobenzoxy chloride (0.97 mL) was added dropwise, followed by stirring at 5° C. or below for another hour and dropwise addition of a third portion of carbobenzoxy chloride (0.97 mL). The resulting mixture was stirred at 5° C. or below for 1 hour and then at room temperature for 1 hour. Subsequently, the reaction mixture was extracted with dichloromethane (2×100 mL). The dichloromethane layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=1:1->ethyl acetate:methanol=20:1) to give (3R,4R)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol as a milky white tar-like material (1.18 g).
Reaction SMILES: [N+:1](=[C:3](C=O)[CH:4]=O)=[N-:2].[Cl-].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:14]2[CH:4]=[CH:3][N:1]=[N:2]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: [N-]=[N+]=C(C=O)C=O
Reactant: COc1ccc(N)cc1OC
Agent: [Cl-]
Product: COc1ccc(-n2ccnn2)cc1OC

Procedure:
The derivative (114m) was prepared with 80.0% of output, as of the reaction of diazomalonaldehyde with the 3,4-dimethoxyaniline chloride, thus obtaining an amorphous yellow solid with fusion point at 170.0-171.0° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc[nH]c(=O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccnc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
A 0.77 g quantity of 4-acetoxy-2-pyridone was suspended in 30 ml of dioxane. To the suspension were added 2.09 ml of triethylamine and 0.58 ml of benzoyl chloride and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography using, as an eluent, chloroform, giving 0.95 g of the title compound in a yield of 73%.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:24][CH:25]([CH3:27])[CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.[NH2:28]/[C:29](/[CH3:33])=[CH:30]\[C:31]#[N:32]>C(O)C>[C:31]([C:30]1[CH:16]([C:15]2[C:9]3[S:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=2)[C:19]([C:18]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[C:20]([CH3:22])[NH:28][C:29]=1[CH3:33])#[N:32]
Reactant: O=Cc1cccc2nc(-c3ccccc3)sc12
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: C/C(N)=C/C#N
Solvent: CCO
Product: CC1=C(C#N)C(c2cccc3nc(-c4ccccc4)sc23)C(C(=O)OC(C)C)=C(C)N1
Yield: 28 %

Procedure:
10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol of isopropyl acetoacetate and 10 mmol of 3-aminocrotononitrile are boiled overnight in 20 ml of ethanol, the mixture is concentrated and the residue is purified on a silica gel column (cyclohexane/ethyl acetate=6:4) Yield: 28% of theory M.p.: 218° C.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[CH2:6]1[C@@H:16]2[C@H:10]([CH:11]=[CH:12][C:13]3[C:14]4[N:15]2[C:17]2[CH:26]=[CH:25][N:24]=[CH:23][C:18]=2[C:19]=4[CH2:20][CH2:21][CH:22]=3)[CH2:9][CH2:8][CH2:7]1>C(O)C>[CH2:6]1[CH:16]2[CH:10]([CH:11]=[CH:12][C:13]3[C:14]4[N:15]2[C:17]2[CH:26]=[CH:25][N:24]=[CH:23][C:18]=2[C:19]=4[CH2:20][CH2:21][CH:22]=3)[CH2:9][CH:8]([CH2:2][CH2:1][C:3](=[O:4])[CH3:5])[CH2:7]1
Reactant: C=CC(C)=O
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Solvent: CCO
Product: CC(=O)CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Reaction time: 96 h
Yield: 86.5 %

Procedure:
2.3 grams of methyl vinyl ketone was added to a solution of 8.3 grams of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine in 400 ml. of ethanol. The mixture was permitted to stand at room temperature for four days, after which an additional 2.6 grams of methyl vinyl ketone was added. This mixture was permitted to stand at room temperature for three days, and was then filtered, evaporated to dryness in vacuo, and triturated with pentane. The resulting solid was recrystallized from ethanol to yield 9 grams of the title compound with m.p. 102.5° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[C:33]3[C:32]4[CH:31]=[C:30]([C:34]5[CH:39]=[CH:38][C:37]([O:40][C:41]6[N:46]=[CH:45][CH:44]=[CH:43][N:42]=6)=[CH:36][C:35]=5[Cl:47])[C:29]([F:48])=[CH:28][C:27]=4[N:26]=[CH:25][C:24]=3[N:23]=[C:22]2[CH3:49])[C@@H:17]([F:50])[CH2:16]1)=O)(C)(C)C.CO.C(Cl)Cl>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:47][C:35]1[CH:36]=[C:37]([O:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:38]=[CH:39][C:34]=1[C:30]1[C:29]([F:48])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:23]=[C:22]([CH3:49])[N:21]([C@H:18]4[CH2:19][CH2:20][NH:15][CH2:16][C@@H:17]4[F:50])[C:33]=3[C:32]=2[CH:31]=1
Reactant: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCNC[C@@H]1F
Reaction time: 3 h

Procedure:
TFA (20 ml) was added drop wise to a solution of (3S,4S)-tert-butyl-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate (10 g, 0.0164 mol) in dry DCM (150 mL) at 0° C. under N2 atmosphere. After addition completed, the reaction mixture allowed to RT and stirred for 3 h. The reaction was monitored by TLC (5% MeOH/DCM), after completion of reaction by TLC, the volatiles were concentrated under vacuum. The obtained residue was triturated with diethyl ether. The solid was filtered and dried under vacuum to afford TFA salt of 8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoropiperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline (11 g, quantitative). LCMS: 99.41%, m/z=507.1 (M+1) (Free base); HPLC: 96.43%, 6.002 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[N:15]([CH2:38][CH3:39])[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(nc(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)c3ncn(C)c32)[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc2n1CC
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylate (example 1F, 5.046 g, 9.90 mmol) in DMF (49.5 mL) was added ethyl iodide (1.601 mL, 19.81 mmol) and cesium carbonate (6.45 g, 19.81 mmol). The reaction mixture was heated at 60° C. 60 min and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and vacuum filtered to remove cesium carbonate. Saturated aqueous sodium bicarbonate was added and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with 10% lithium chloride (3×), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Crude product was carried forward.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CCO.C1COCC1.O>[CH:21]1([C:19]([NH:18][CH:15]2[CH2:14][CH2:13][CH:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)=[O:20])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Reaction time: 17 h

Procedure:
To a solution of 4-[4-(cyclopropanecarbonylamino)cyclohexyloxy]benzoic acid ethyl ester (4.75 g, 14.3 mmol) in EtOH (30 mL) and THF (10 mL) was added NaOH (2.29 g, 57.3 mmol) in 10 ml of water. Stirring was continued at ambient for 17 hrs. The solvents were removed under vacuum, water (50 mL) was added and the whole extracted with EtOAc. The aqueous layer was acidified to pH ˜2 with 2N HCl and the white precipitate obtained was filtered off and washed with hexane affording 4.0 g (92%) of 4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][N:32]1[C:36](=[O:37])[C:35]2[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]1=[O:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
tert-Butyl(2-hydroxyethyl)carbamate (1.61 g, 10.0 mmol) was stirred under an argon atmosphere at room temperature with dehydrated tetrahydrofuran (50 mL). Then, triphenylphosphine (2.75 g) and N-hydroxyphthalimide (Pht-OH, 1.71 g) were added. After the reaction mixture was under ice cooling, diethyl azodicarboxylate (DEAD, 1.82 g) was added dropwise gradually, followed by stirring at room temperature for 24 hours. After completion of the reaction, the residue resulting from distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→1/1) to afford 2.61 g of the title compound (yield 85.2%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: CCCCCOC(=O)CCl
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (3 g) in dimethylformamide (100 ml), anhydrous potassium carbonate (0.8 g) and then amyl chloroacetate (1.9 g) were added, and the resultant mixture was heated at 70° to 80° C. for 3 hours. The reaction mixture was cooled to room temperature, admixed with water and extracted with diethyl ether. The etheral layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the compound (I) (1.8 g).
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].CC(S)[C:13]([O-:15])=[O:14].[CH3:17]O>>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([S:4][CH3:5])[S:2][C:1]=1[C:13]([O:15][CH3:17])=[O:14]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CO
Reactant: CC(S)C(=O)[O-]
Product: COC(=O)c1sc(SC)c(C#N)c1N
Yield: 99 %

Procedure:
A mixture of [bis(methylsulfanyl)methylene]malononitrile (40 g, 230 mmol), methylthioglycolate (21 mL, 230 mmol) and TEA (24 mL, 173 mmol) in MeOH (600 mL) was allowed to stir at reflux for 2 h. The reaction mixture was allowed to cool overnight and the precipitate was filtered off, washed with cold MeOH (×3) to give methyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (52.4 g, 99%). LCMS: (AA) ES+ 229.2. 1H NMR (400 MHz, d6-DMSO) δ: 3.74 s, 3H) and 2.70 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[CH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([NH:8][C@H:9]([CH:10]1[CH2:11][O:27]1)[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C=C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C1CO1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
2.6 g of Boc-1(S)-cyclohexylmethylprop-2-en-1-ylamine are dissolved in 50 ml of CH2Cl2, and 1.9 g of m-chloroperbenzoic acid in 50 ml of CH2Cl2 are added dropwise at 0° C. The reaction solution is stirred at R.T. for 36 h and is then extracted first with 100 ml of 5% strength aqueous Na2SO3 solution and then with 100 ml of saturated aqueous Na2CO3 solution. Drying over Na2SO4 and concentration in vacuo are followed by chromatography on silica gel (mobile phase MTB/cyclohexane 1:1) resulting in the title compound as a colorless oil, diastereomer ratio 3:1 to 5:1.
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=NOC(C4C(C(F)(F)F)=C(C5C=CC=CC=5)ON=4)=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(=NC(CCC2C=C3C(=CC=2)C2[S:82][C:81]([C:87]4[O:91][N:90]=[C:89]([C:92]5[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=5)[C:88]=4[C:98]([F:101])([F:100])[F:99])=[N:80]C=2CC3)C(OCC)=O)C2C=CC=CC=2)C=CC=CC=1>>[C:8]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2[S:82][C:81]([C:87]4[O:91][N:90]=[C:89]([C:92]5[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=5)[C:88]=4[C:98]([F:101])([F:100])[F:99])=[N:80][C:28]=2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)N=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)N=C(c1ccccc1)c1ccccc1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 93A employing ethyl 2-(diphenylmethyleneamino)-4-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)butanoate (Preparation 119A) as a starting material. The compound had an LC/MS M+1=706.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (80/20, EtOAc/hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O. The product was isolated by filtration and dried in vacuo to give 6-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-nicotinamide as a white solid (0.77 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.56 min (99.14%); mp: 174-176° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.54-2.73 (m, 3H), 4.34 (dd, J=7.2, 14.1 Hz, 2H), 4.62 (d, J=6.0 Hz, 2H), 6.88 (d, J=8.7 Hz, 1H), 7.77-7.83 (m, 3H), 8.14 (dd, J=2.4, 8.7 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 9.20 (t, J=6.0 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.40, 21.00, 28.60, 29.10, 42.50, 58.70, 61.80, 110.30, 121.60, 123.00, 123.20, 129.60, 131.40, 133.40, 138.10, 147.10, 147.30, 164.70, 165.00, 167.70, 167.90, 172.10, 172.20; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.3H2O: C, 60.60; H, 5.00; N, 12.29. Found: C, 60.24; H, 4.86; N, 12.15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([O-])=[O:20].[K+].CC(OC(C)=O)=O>CC#N>[O:17]=[C:10]1[NH:9][C:8]([C:4]2[CH:3]=[C:2]([O:1][C:19](=[O:20])[CH3:18])[CH:7]=[CH:6][CH:5]=2)=[N:13][C:12]2[CH:14]=[CH:15][S:16][C:11]1=2
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1

Procedure:
A mixture of 2-(3-hydroxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 26, (10.95 g, 44.8 mmol), KOAc (6.6 g, 67.2 mmol) and Ac2O (16.5 mL, 0.175 mol) in MeCN (150 mL) were heated at reflux temperature for 24 h. The cooled reaction mixture was poured onto water (500 mL) and the resulting precipitate was collected by filtration. This was then washed with water and dried to furnish acetic acid 3-(4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidin-2-yl)-phenyl ester, 27, as a grey solid (10.87 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36].CCN(CC)CC>C(Cl)Cl>[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)=[O:36]
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cnn(C)c5Cl)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a mixture of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.41 mmol) and 5-chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.073 g, 0.41 mmol) in CH2Cl2 (50 mL), was added Et3N (0.086 mL, 0.62 mmol) and the reaction stirred under nitrogen at room temperature for 1 hour. The residue was concentrated and purified by flash chromatography on silica gel, eluting with 70% CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a white solid (0.159 g, 76%). 1H NMR (500 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.77 (s, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.80-3.87 (m, 6H), 3.63-3.80 (m, 4H), 3.38-3.44 (m, 4H). APCI MS m/z 509 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:49](Cl)(=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2cc(S(=O)(=O)Oc3c(C)cc(-c4c5ccccc5c(Br)c5sc(C)c(C)c45)cc3C)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
At ambient temperature, to a stirred solution containing 4-[4-(9-bromo-2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.402 g, 0.602 mmol) and pyridine (0.292 mL, 3.61 mmol) in CH2Cl2 (6.02 mL) was added a solution of p-anisoyl chloride (0.208 g, 1.20 mmol) in CH2Cl2 (1.20 mL). After 18 h, the reaction was quenched with H2O (30 mL) and extracted with ether. The combined ethereal extracts were washed with sat. aq. NaHCO3 (3×), with sat. aq. CuSO4 (3×), with brine (3×), dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 15% acetone/hexane to give 0.354 g (73%) of the title compound. 1H NMR (DMSO-d6) δ 1.33 (s, 9 H), 1.54 (s, 3 H), 2.16 (s, 6 H), 2.34 (s, 3 H), 3.90 (s, 3 H), 7.13-7.19 (m, 4 H), 7.46-7.48 (m, 2 H), 7.60-7.70 (m, 1 H), 8.08-8.13 (m, 4 H), 8.20 (d, 2 H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[N:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]5[CH:34]=[CH:33][C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[N:28]6)=[CH:40][CH:39]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-n2cccn2)cc1

Procedure:
The title compound, white solid (112 mg, 90%), MS (ISP) m/z=499.3 [(M+H)+], mp 258.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-pyrazol-1-yl-benzoic acid.