Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2.[CH:21]([O:23]CCCC)=[CH2:22].C([O-])(O)=O.[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2)(=[O:23])[CH3:22]
Reactant: C=COCCCC
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(Br)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Product: CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1
Temperature: 96 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
In 100 mL autoclave vessel a solution of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Intermediate 1, 10 g, 29.4 mmol) in ethanol (35 mL) was degassed with nitrogen gas for 30 minutes. To the resulting reaction mixture was added TEA (7.37 mL, 52.9 mmol), butyl vinyl ether (7.60 mL, 58.8 mmol), dppp (0.727 g, 1.8 mmol) followed by addition of Pd(OAc)2 (0.198 g, 0.9 mmol) at room temperature. Reaction mixture was heated at 96° C. for 16 hours in autoclave. After complete consumption of starting material, reaction mixture was quenched with addition of 1N HCl (10 mL) to adjust pH 2-3 then reaction mixture was stirred for 2 hours. The pH of reaction mixture was adjusted to 7 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with brine (250 mL), dried over sodium sulfate and concentrated under reduced pressure to get crude compound as dark brown sticky oil 12 g as crude material. The crude was purified by column chromatography on silica gel using 230-400 silica mesh. Desired compound was eluted in 30% ethyl acetate in n-hexane to give (8.4 g) compound as off white sticky semi-solid. 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 2.61 (s, 3H), 4.13 (d, J=9.64 Hz, 2H), 4.32 (d, J=9.52 Hz, 2H), 5.14 (s, 2H), 7.54 (d, J=7.96 Hz, 1H), 7.80 (s, 1H), 7.97 (d, J=7.92 Hz, 1H); VETERINARY (m/z): 304.0 (M+H).
Reaction SMILES: C(OC([S:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)=S)C.[OH-].[K+]>C(O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([SH:6])=[C:8]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:9]=1
Reactant: CCOC(=S)Sc1ccc(C)cc1COC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S)c(COC2CCCCO2)c1

Procedure:
13.7 g (42 mmol) of the compound from Example 8 are heated overnight under reflux with 9.5 g (0.17 mol) of potassium hydroxide in 70 ml of ethanol. The mixture is concentrated in vacuo, the residue is dissolved in water, the solution is washed with ether, and the aqueous phase is acidified with acetic acid and washed with ether. This ether phase is washed with water, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:28])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:15][C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:1]1([N:4]2[C:14]3[C:13](=[CH:18][C:17]([F:19])=[C:16]([CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[CH:15]=3)[C:12](=[O:28])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2cc(C3CCN(C)CC3)c(F)cc2c1=O
Temperature: 65 °C

Procedure:
A solution of 3.91 g (10 mmoles) of ethyl α-[(cyclopropylamino)methylene]-2,5-difluoro-4-(1-methyl-4-piperidinyl)-β-oxobenzenepropanoate in 50 ml of t-butyl alcohol was treated with 1.23 g (11 mmoles) of potassium t-butoxide and heated at 65° C. for 11/2 hours. The mixture was evaporated under vacuum and the residue was stirred in 50 ml of water and neutralized with 1 N HCl. After extraction with chloroform the organic layer was dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]([C:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Na+].[OH-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[N:12]=[CH:13][CH:14]=[N:15]2)[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)[O-])c(-n2nccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C(=O)O)c(-n2nccn2)c1

Procedure:
(sodium 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinate). To a solution of the title compound of Step A (489 mg, 2.6 mmol) in EtOH (7 mL) was added 4 N NaOH (660 μL, 2.6 mmol). The mixture was heated at 100° C. for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:20]2[CH:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[S:23][C:19]=2[N:18]2[C:34]([CH3:37])=[N:35][N:36]=[C:17]2[CH:16]([CH3:38])[N:15]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:20]2[CH:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=3)[S:23][C:19]=2[N:18]2[C:34]([CH3:37])=[N:35][N:36]=[C:17]2[CH:16]([CH3:38])[N:15]=1
Reactant: Cc1nnc2n1-c1sc(CCc3ccc(CO)cc3)cc1C(c1ccccc1Cl)=NC2C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(CCc3ccc(C=O)cc3)cc1C(c1ccccc1Cl)=NC2C
Yield: 57.4 %

Procedure:
To a suspension of 15 g of dry sellaite and 12 g of dry pyridine in 150 ml of methylene chloride is added 7.4 g of chromic anhydride under ice-cooling with stirring and then stirred for 20 minutes. To the mixture is added a solution of 7 g of 4-(2-chlorophenyl)-2-[2(4-hydroxymethylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, which was prepared by Example 1, in 20 ml of methylene chloride dropwise with stirring and stirred for an hour. The methylene chloride layer is separated by filtration and the sellaite is well washed with chloroform. The mixture of the washings and the methylene chloride solution is thoroughly washed with water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the resulting oil is subjected to chromatography on silica gel to give 4 g of 4-(2-chlorophenyl)-2-[2-(4-formylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([NH2:31])=[CH:26][N:25]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:15][C:26]3[N:25]=[C:24]([Cl:23])[N:29]=[CH:28][C:27]=3[N:31]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncc2nc(-c3ccc(OCc4ccccc4)cc3)oc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 298.1 %

Procedure:
A mixture of 4-(benzyloxy)benzoic acid (1.04 g) and phosphorus oxychloride (12.2 mL) was stirred at room temperature for 5 min, and 2,4-dichloropyrimidin-5-amine (500 mg) was added thereto, and the obtained mixture was stirred at 100° C. for 2 hr. The reaction mixture was added to 1M aqueous sodium hydroxide solution at 0° C., and the precipitate was collected by filtration, and dissolved in THF and ethyl acetate. The obtained solution was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (3.07 g) as a mixture with impurity. A mixture of 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (100 mg, a mixture with impurity), tert-butyl (2S)-but-3-yn-2-ylcarbamate (50.1 mg), dichlorobis(triphenylphosphine)palladium(II) (10.4 mg), copper(I) iodide (5.64 mg), triethylamine (0.041 mL) and DMF (2 mL) was stirred at 100° C. for 6 hr under an argon atmosphere. In another reaction container, A mixture of 2-(4-(benzyloxy)phenyl)-5-chloro[1,3]oxazolo[5,4-d]pyrimidine (100 mg, a mixture with impurity), tert-butyl (2S)-but-3-yn-2-ylcarbamate (50.1 mg), dichlorobis(triphenylphosphine)palladium(II) (10.4 mg), copper(I) iodide (5.64 mg), triethylamine (0.041 mL) and toluene (2 mL) was stirred at 100° C. for 6 hr under an argon atmosphere. The two reaction mixtures were combined, water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (44.4 mg).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1.[C:25]([O-])(=[O:27])C.[Na+]>CN(C=O)C>[CH:25]([C:13]1[CH:12]=[CH:11][C:10]([CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:9][C:8]=1[O:7][CH3:6])=[O:27]
Reactant: COc1cccc(CNCCOC(=O)C(C)(C)C)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=O
Reaction time: 0.67 h

Procedure:
POCl3 (5.8 g, 37.7 mmol) was added to 20 ml of DMF in an ice bath. After 40 minutes, 2,2-dimethylpropionic acid 2-[(3-methoxyphenyl)methylamino]ethyl ester (10 g, 37.7 mmol) dissolved in DMF (10 ml) was added dropwise. After the mixture was stirred for 16 hours, an aqueous sodium acetate solution (20%, 100 ml) was added dropwise thereto and the oily matter was subjected to extraction with ethyl acetate. Washing was performed with a saturated aqueous NaHCO3 solution (100 ml) and then with a saturated saline solution (100 ml). After drying over Na2SO4 and concentration, the residue was purified by silica gel chromatography to give a light yellow crystal (yield: 8.7 g (78.9%)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)[CH2:26][CH2:27][OH:28].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:28][CH2:27][CH2:26][CH:25]([NH:24][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[CH:11]=1)=[O:23])[C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: NC(CCO)c1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NC(CCO)c3ccc(C(F)(F)F)nc3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added 3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (47 mg, 0.21 mmol) (WO 2008/130481), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred for 16 hours at 30° C. The reaction mixture was purified by preparative HPLC to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.O.[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[C:15]=[S:16]
Reactant: N#Cc1ncc(N)cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Temperature: 22 °C
Reaction time: 2 h

Procedure:
5-Amino-3-(trifluoromethyl)pyridine-2-carbonitrile 8 (1.141 g, 6.1 mmol) is mixed with chloroform (5 ml) and water (40 ml) to give a white suspension. Thiophosgene (0.701 ml, 9.15 mmol) is added and the reaction stirred for 2 hours at 22° C. to give a clear biphasic system. Chloroform (20 ml) is added and the phases are separated. The aqueous layer is extracted with chloroform (30 ml) and the combined organic is washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and the solvent is removed under reduced pressure. The crude 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile 9 is dried under vacuum and used as such in the next step, for example, in the step described in Example 8 below.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1.C[O:24][B:25](OC)[O:26]C>C1COCC1.CCOCC.O.CO>[CH3:22][N:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([B:25]([OH:26])[OH:24])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: COB(OC)OC
Reactant: Cn1ccc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(B(O)O)cc21
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 1.7 mL, 27.2 mmol) was added to 6-bromo-1-methyl indole (5.0 g, 23.8 mmol) in dry THF (100 mL) at −78° C. over 30 min. After 30 min, trimethylborate (2.93 g, 28.2 mmol) in dry THF (25 mL) was added. Stirring was continued at −78° C. for 30 min. Methanol (12.5 mL) and water (12.5 mL) were added, and the mixture was stirred at room temperature for 3 h. It was diluted with ether (100 mL), and washed with sulfuric acid (1 N, 2×100 mL) and water (2×100 mL). The aqueous layer was back extracted with ether (2 ×100 mL). The combined organic extracts were dried (MgSO4), filtered over a pad of silica gel and the pad was washed with ether (100 mL). The filtrate was concentrated and the crude product was chromatographed over silica gel with 10% to 25% ethyl acetate/hexanes to give 1-methyl-1H-indol-6-yl-boronic acid (2.6 g, 62.5%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2C2C=CC=C(C(OCC)OCC)C=2)[CH:8]=[CH:9][CH:10]=1)C.[C:41](=[O:44])([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][C:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])([C:5]4[CH:10]=[C:9]([CH:8]=[CH:7][CH:6]=4)[CH:41]=[O:44])[CH2:12][C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Agent: Cl
Agent: [K+]
Product: O=Cc1cccc(C2(c3cccc(C=O)c3)Cc3n[nH]c(=O)c4cccc(c34)N2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for 2 hr. Then the mixture was adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,8-diyl)dibenzaldehyde (160 mg, yield 88%) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.57-4.59 (d, J=9.6 Hz, 1H), 4.98-5.00 (d, J=9.2 Hz, 1H), 7.20-7.22 (d, J=7.6 Hz, 1H), 7.42-7.52 (m, 5H), 7.60-7.77 (m, 5H), 7.89 (s, 1H), 9.90 (s, 1H), 9.93 (s, 1H), 12.08 (s, 1H); LC-MS (ESI) m/z: 396(M+1)+.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]2[CH2:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([F:18])[C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21](=O)[CH2:22][CH3:23].[BH3-]C#N.[Na+]>CO>[CH:1]1([N:7]([C@@H:8]2[CH2:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([F:18])[C:11]=3[O:10][CH2:9]2)[CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCCC1)CO2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN(C1CCCCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of (R)-3-(N-cyclohexylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran in methanol (25 mL) were propanal (1.3 g, 23 mmol) and NaCNBH3 (0.15 g, 2.3 mmol) added. The solution was stirred overnight to give the desired compound in a 97% yield according to GC. The solvent was removed in vacuo and the residue was worked up by extraction to give 0.7 g of the title compound as a colorless oil. GC/MS (70 eV) M=321 (40%).
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:27])[N:12]2[C:15](=[C:24](O)[CH3:25])[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(C1SC2C(C(=O)[N:44]2[C:47](=C(OS(C)(=O)=O)C)[C:48]([O:50][CH2:51][C:52](Cl)(Cl)Cl)=O)N=1)C1C=CC=CC=1.N1CCOCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:27])[N:12]2[C:15](=[C:24]([N:44]2[CH2:47][CH2:48][O:50][CH2:51][CH2:52]2)[CH3:25])[C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: CC(O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC(=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 0.67 h

Procedure:
To a solution of 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (450 mg) in methylene chloride (7 ml) are added methanesulfonyl chloride (0.093 ml) and triethylamine (0.48 ml) at -25° C., and the mixture is kept at the same temperature for 40 minutes. To the produced solution of 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate is added dropwise morpholine (0.112 ml), and the mixture is stirred for 1.3 hours. The reaction mixture is washed with water, dried, and evaporated to give residue which is purified by chromatography over silica gel containing 10% water to give 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate (205 mg).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]Cl)=[CH:15][CH:14]=1>C(Cl)(Cl)(Cl)Cl.[Fe]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)=[CH:15][CH:14]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: ClSc1ccc(Cl)cc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Sc2ccc(-c3ccccc3)s2)cc1
Reaction time: 168 h
Yield: 52.8 %

Procedure:
A solution of 40 g (0.250 mole) of 2-phenylthiophene in 200 ml of carbon tetrachloride was treated at room temperature with 45 g (0.252 mole) of p-chlorobenzenesulfenyl chloride. Iron powder (0.1 g) was added and the reaction mixture was allowed to stand for seven days at room temperature. Filtration removed a small amount of insoluble material. Evaporation of the filtrate gave a residue of 79.8 g of crude product, m.p. 85°-87° C. Recrystallization of the residue from 400 ml of absolute ethanol gave 40 g (53%) of 2-(p-chlorophenylthio)-5-phenylthiophene, m.p. 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>C(Cl)(Cl)Cl>[CH2:30]([O:32][CH2:33][C:34]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:31]
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (9.25 g, 30.7 mmol) in chloroform (100 mL) was cooled to 0° C.; triethylamine (5.13 mL, 36.8 mmol) was added. Ethoxyacetyl chloride (4.51 g, 36.8 mmol) was then added dropwise over a period of five minutes. The reaction was allowed to warm to ambient temperature, heated at reflux overnight, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol) to provide 7.73 g of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Li+].[OH-]>CO>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:24])=[O:2])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
t-Boc-gly-phe-OCH3, 6a, (9.2 g, 2.7 ×10-2 mole), 1M aqueous LiOH (30 ml, 3.0 ×10-2 mole), and methanol (100 ml) are stirred at room temperature for 2 hours. Most of the methanol is evaporated. The concentrate is diluted with water (10 ml) and transferred to a separatory funnel. The mixture is then acidified with 1M aqueous HCl (50 ml) and the aqueous acidic mixture subsequently extracted with CHCl3 (4 times). The combined CHCl3 extracts are washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives a foam which when triturated with Et2O/hexane affords 7a as a colorless solid which crystallizes from ethyl acetate/hexane as colorless needles: 6.3 g (71%), m.p. 138-141° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CCN(CCCC(N[C:25]1[CH:26]=[C:27](/C=C/C2C=CC=CC=2Cl)[N:28]=[C:29]2[CH:34]=[C:33](Cl)[CH:32]=[CH:31][C:30]=12)C)CC.C([O-])=O.[NH4+]>CO.[Pd]>[N:28]1[C:29]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[C:26]([NH:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=2)[CH:27]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1ccc(CCNc2cnc3ccccc3c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 10.4 mmol 4-(trifluoromethyl)phenylacetonitrile (commercially available) and 3.5 eq. aminoquinoline in MeOH (10 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (100 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, CH2Cl2/MeOH) afforded the title compound (73%) as a yellow oil. MS m/e: 317.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)[C:13]=3[CH:20]=2)=[O:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1
Product: O=C(c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1)N1CCOCC1

Procedure:
150 mg (458 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to example 30) were transformed in analogy to example 4 using morpholine to give after working up and purification 25.0 mg (12%) of the title compound.