Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:13])(O)[CH3:11])=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])OCC[O:17]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.CC1C=CC=CC=1>[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:13][CH:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][O:17]1
Reactant: Clc1ccc(C2(CBr)OCCO2)c(Cl)c1
Reactant: CC(O)(O)CCc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Clc1ccc(CCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
A mixture of 11.2 parts of 1-[2-(4-chlorophenyl)ethyl]-ethanediol, 15.6 parts of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane, 4 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene is stirred and refluxed for 5 days with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred with silica gel. The latter is filtered off and the filtrate is evaporated, yielding 2-(bromomethyl)-4-[2-(4-chlorophenyl)ethyl]-2-(2,4-dichlorophenyl)-1,3-dioxolane as a residue.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[NH2:6][C@@H:7]([C:12]([NH2:14])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10].Cl.Cl[C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][CH:31]=[CH:30]3)[N:18]=1.[Cl-].[Na+]>C(OCC)(=O)C.O.O1CCOCC1>[C:21]([C:20]1[CH:23]=[C:24]([F:25])[C:17]([NH:6][C@H:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:12]([NH2:14])=[O:13])=[N:18][C:19]=1[NH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[CH:30]2)#[N:22]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@@H](Nc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F)C(N)=O
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Calcium carbonate (138 mg) and D-leucinamide•hydrochloride (83 mg) were added to a 1,4-dioxane (1 ml) solution containing 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (30 mg), followed by reflux for 15 hours. The reaction mixture was cooled to room temperature, and water, sodium chloride, and ethyl acetate were added. The organic layer was collected and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether was added to the obtained residue, solid matter was collected by filtration, and a yellow solid of (2R)-2-(5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-ylamino)-4-methylpentanamide (33 mg) was thus obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=1)[C:9](Cl)=[O:10])(=[O:3])[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=1)[C:9]([NH:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23])=[O:10])(=[O:3])[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)Cl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc(C(C)=O)ccc1OCC

Procedure:
The title compound was prepared from 5-acetyl-2-ethoxybenzoyl chloride and 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide following the procedure of Preparation 6, and was obtained as a white solid (60%), m.p. 225°-227° C. Found: C,61.35; H,6.25; N,15.07. C19H24N4O4 requires C,61.28; H,6.50; N,15.04%.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(C3CCCC3)c2n1

Procedure:
A solution of 8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (10), (3.5 mmol) and MCPBA (5.25 mmol) in CH2Cl2 was stirred at room temperature for about 12 h. After completion of the reaction, the reaction mixture was washed with saturated NaHCO3. The organic layer was dried over Na2SO4, filtered away from the drying agent, and concentrated to give the desired product (11) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Si:20]([O:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH2:31]1)([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCCNC1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: CC(C)(C)[Si](C)(C)OCCC1CCCN(c2cnc(-c3ccccc3)c(-c3ccccc3)n2)C1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and (±)-3-[2-(tert-butyldimethylsilyloxy)ethyl]piperidine was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7](O)(=O)[C:8](O)=[O:9].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:8]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:9])[CH3:7]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise acetyl chloride (0.071 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.360 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.243 g colorless crystals. Mp 176° C. Mass spectrum, m+ =371. Anal (C22H31N5O6) theory C, 57.25; H, 6.77; N, 15.17; found C, 56.95; H, 6.74; N, 14.99.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:12]([NH2:14])=O)[C:4]=2[N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:12]#[N:14])[C:4]=2[N:3]=1
Reactant: Cc1ccc2c(n1)C(C(N)=O)CCC2
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Cc1ccc2c(n1)C(C#N)CCC2

Procedure:
2-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide was treated with P2S5 to give 2-methyl-8-cyano-5,6,7,8-tetrahydroquinoline which was treated with H2S (both reactions being carried out by the method described in Example 8 to give the title compound as colourless needles from ethylacetate (28%) m.p. 98° (Found: C, 64.32; H, 6.93; N, 13.52%, C11H14N2S requires: C, 64.04; H, 6.84; N, 13.58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:34]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:3][CH2:4]4)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.31 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile and 287 mg (1.86 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 120 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-(2-methoxyethoxy)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 238-241° C.
Reaction SMILES: ClCCl.Cl[C:5]1[C:6]([F:34])=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH2:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:9].C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].O>[F:34][C:6]1[CH:5]=[CH:33][CH:32]=[CH:31][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH2:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)c2F)C(COc2cccnc2)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2F)C(COc2cccnc2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (18 mg, 0.022 mmol) was added to a mixture of tert-butyl 4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (100 mg, 0.222 mmol), benzeneboronic acid (81 mg, 0.67 mmol) and sodium carbonate (71 mg, 0.67 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 110° C. overnight. Additional portions of the palladium catalyst, boronic acid and sodium carbonate were added and heating continued at 110° C. After stirring overnight, additional portions of the palladium catalyst, boronic acid and sodium carbonate were again added and heating continued at 110° C. overnight. Upon cooling to room temperature, the reaction mixture was filtered through Celite®, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 115 mg (86%) of the title compound as the TFA salt that was −80% pure by LC-MS. LC-MS: RT=9.06 min, [M+H]+=492.9. 26.3 mg (22%) of tert-butyl 4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate were also isolated as the TFA salt. LC-MS: RT=7.53 min, [M+H]+=416.7.
Reaction SMILES: COCC[O:5][C:6]1[CH:32]=[CH:31][C:9]2[N:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:5][C:6]1[CH:32]=[CH:31][C:9]2[N:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:23][S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])[CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(Oc1cccc2ccc(-n3cnc4cc(O)ccc43)nc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
Trifluoro-methanesulfonic acid 2-[5-(2-methoxy-ethoxy]benzoimidazol-1-yl]-quinolin-8-yl ester 77E (2.00 g, 4.28 mMol) was suspended in 20 mL of anydrous DCM under an atmosphere of dry N2. To this heterogeneous solution was added 12.9 mL of a solution of 1 M borontribromide in DCM and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was then poured into ice water. The resulting heterogeneous mixture was neutralised with the addition of NaHCO3 and then partitioned between isopropanol/DCM (1882) and aqueous saturated NaHCO3. The organic layer was washed again aqueous saturated NaHCO3, dried over Na2SO4, filtered, concentrated under vacuum to give 890 mg of a brownish yellow solid as the title compound 116A.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:28][CH2:27][CH:26]([C:29]#[N:30])[CH2:25][CH2:24]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: N#CC1CCNCC1
Product: N#CC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and piperidine-4-carbonitrile were reacted to give 220. MS: (ESI+)=406.0
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[CH2:10]2)=[O:6])C.[OH-].[Na+].Cl>C(O)C>[ClH:25].[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[CH2:10]2)([OH:6])=[O:4]
Reactant: CCOC(=O)c1ccc2c(c1)CN(Cc1ccc(Cl)cc1Cl)C(C)=N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=Nc2ccc(C(=O)O)cc2CN1Cc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
6-(Ethoxycarbonyl)-3-(2,4-dichlorobenzyl)-3,4-dihydro-2-methylquinazoline hydrochloride (0.68 g) in a mixture of a 10% aqueous sodium hydroxide solution (5 ml) and ethanol (10 ml) was stirred at 60° C. for 1 hr. After standing cool the reaction mixture, concentrated hydrochloric acid (5 ml) was added and the precipitate was collected by filtration. The precipitated was washed with toluene and 2-propanol and dried to give the objective compound (0.41 g) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10]>CO.[OH-].[Pd+2].[OH-].[C]>[O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(CN1CCOCC1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCOCC1=O
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Under an argon atmosphere, to a solution of benzyl (3-oxomorpholin-4-yl)acetate (319 mg, 1.3 mmol) in methanol (5 ml) was added 20% palladium hydroxide-carbon (64 mg) at room temperature. Then, the mixture was stirred for 2 hr under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (206 mg, yield over weight).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[OH-].[Li+].C(O)=O>O1CCOCC1.O>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=CO
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1occc1-2
Temperature: 90 °C
Yield: 19.8 %

Procedure:
A mixture of methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 45, 0.130 g) and lithium hydroxide (0.105 g) in dioxane (3 mL) and water (1 mL) was heated at 90° C. for 20 hours. After cooling, the mixture was diluted with water (20 mL) and acidified to pH5-6 with formic acid. This was extracted into ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-10%. The product was triturated with diethyl ether/ethyl acetate (1:1) to give 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylic acid (0.025 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(=O)C.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2NC1=O
Temperature: 52.5 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
In 1.2 g of acetic acid were dissolved 1.39 g of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine and 3.9 g of cyclohexanone. To the resulting solution was added 302 mg of 10% palladium carbon. Under a hydrogen pressure of 10 kg/cm2, the mixture was stirred at 50 to 55° C. for 12 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was filtered through Celite. Water was added to the filtrate and crystals so precipitated were collected by filtration with suction. The resulting crystals were recrystallized from a mixed solvent of ethanol and water, whereby 1.63 g of the title compound was obtained.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:14]=[C:13](C(O)=O)[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:43]>CCOC(C)=O.CCCCCC.CCN(CC)CC.C(O)CCC>[ClH:43].[C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:14]=[C:13]([NH2:21])[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=Cc2cccc(C(=O)O)n2)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCCCCC
Product: Cc1ccc(C=Cc2cccc(N)n2)cc1

Procedure:
In a variation to the procedure referred to in example 1, 6-(2-p-tolyl-vinyl)-pyridine-2-carboxylic acid (2.81 g, 11.7 mmol) was brought to reaction with triethylamine (1.21 g, 12.0 mmol), diphenyl phosphoryl azide (3.56 g, 12.9 mmol) and butanol (33 ml). After extractive workup the residue was refluxed (4 hr) with 3N HCl. Extractive workup and chromatography (SiO2 with AcOEt/hexane/NEt3=10:20:1) afforded the title compound as an oil which was crystallized as the yellow hydrochloride salt (0.95 g, 33%). Mp.>250° C. (MeOH/Et2O), MS: m/e=210 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1>[Cu]I.C(#N)C>[N:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C#CCCCCO
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Product: OCCCCC#Cc1cncnc1
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
A mixture of 5-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicyclohexylamine (4 g) and acetonitrile (50 ml) was de-oxygenated by bubbline nitrogen through the solution for 10 min. BTPC (150 mg) and copper (I) iodide (25 mg) were added and the mixture was heated to 60°-70° under nitrogen for 1 h, cooled and evaporated in vacuo. Ether (175 ml) was added, the mixture filtered and evaporated in vacuo and the residue purified by FCC. Elution with ether followed by System C (19:1-92:8) gave the title compound as a pale yellow oil (3.79 g), t.l.c. (System C 17:3) Rf 0.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3C(OC(C)(C)C)=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(Cl)Cl.O>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 6-(4-methoxyphenyl)-1-tert-butoxycarbonylindole (3.9 g, 12 mmol) in methanol (50 mL) was added 1N methanolic NaOH (60 mL) and CH2Cl2 (20 mL). The reaction was stirred for one hour at ambient temperature and 1.5 hours at reflux. The reaction mixture was cooled to ambient temperature and H2O (50 mL) was added to dissolve all solids. The two-phase mixture was poured into CHCl3 and the layers where separated. The organic phase was washed with brine, dired over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (100 g, 25% ethyl acetate, hexanes) afforded 6-(4-methoxyphenyl)indole as white flakes (2.2 g, 81%).
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=Cc1nccc2ccccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2c(C3OCCO3)nccc2c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A mixture of 1-isoquinolinecarboxaldehyde (7.2 g, 46 mmol), 5.7 g (92 mmol) of ethylene glycol, 200 ml of toluene and 2.3 g (12 mmol) of p-toluenesulfonic acid under argon in a 3 neck-flask equipped with a Dean-Stark Trap was refluxed for 6 h separating the water. The mixture was cooled to room temperature, and poured into an ice-cold 10% sodium carbonate solution. The aqueous layer was extracted with ether, the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 9.3 g of 1-(1,3-dioxolan-2-yl)isoquinoline.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9]C)=O.ClC1C2C=C(OC)C=CC=2SC=1C(Cl)=O.Cl.[NH2:33][CH2:34][CH2:35][SH:36].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C.CO>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:4]2[S:5][C:6]3[C:7](=[O:9])[NH:33][CH2:34][CH2:35][S:36][C:2]=3[C:3]=2[CH:14]=1
Reactant: COC(=O)c1sc2ccc(OC)cc2c1Cl
Reactant: NCCS
Agent: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc3c(c2c1)SCCNC3=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a room temperature solution of methyl 3-chloro-5-methoxy-benzo[b]thiophene-2- carboxylate (500 mg, 1.95 mmols) [prepared by reaction of the known 3-chloro-5-methoxy-benzo[b]thiophene-2-carbonyl chloride with methanol-[J. Med. Chem., 35:958 (1992)]] in 20 mL of DMF is added cysteamine-HCl (885 mg, 7.79 mmol) followed by DBU (2,33 mL, 15.58 mmol) . The reaction mixture is stirred at room temperature for 1.5 hours then warmed to 70° C. The mixture is diluted with ethyl acetate and washed with aqueous HCl, water and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product is recrystallized from hexane and ethyl acetate to provide 2,3-dihydro-9-methoxy[1]benzothieno[2,3- f]-1,4-thiazepin-5(4H)-one in 74% yield; mp 209°-209.5° C.