Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>ClCCl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-4′-cyanobiphenyl (1.03 g, 5.3 mmol) (TCI) was dissolved in a mixture of 8 ml dichloromethane/2 ml pyridine was treated with ethanesulfonyl chloride (0.61 g, 5.3 mmol) and stirred for 18 h at room temperature. The solution was diluted with dichloromethane and washed twice with 1N HCl. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 7.75 (d,2H,J=8 Hz), 7.67 (d,2H,J=8 Hz), 7.60 (d,2H,J=8 Hz), 7.37 (d,2H,J=8 Hz), 6.90 (s,1H), 3.22 (q,2H,J=8 Hz), 1.45 (t,3H,J=8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](N5CCCCC5)=[CH:23][C:22]=4C)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:4][CH:3]=1.C[I:36].[CH3:37][N:38]([CH3:41])[CH:39]=O>>[I-:36].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:37][N+:38]5([CH3:41])[CH2:4][CH2:3][CH2:2][CH2:1][CH2:39]5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(N4CCCCC4)cc2C)CCS3)cc1
Reactant: CI
Reactant: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CCS3)cc1
Product: [I-]

Procedure:
A solution of 7-(4-methylphenyl)-N-(4-piperidino-methyl-phenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (0.08 g) and methyl iodide (0.013 ml) in dimethylformamide (20 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-hexane to give 1-(N-(7-(4-methylphenyl)-2,3-dihydro-1-benzothiepine-4-carbonyl)-4-aminobenzyl)-1-methylpiperidinium iodide (Compound 94) (0.077 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]([NH2:26])=[S:25])=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:28][C:29](=O)[CH3:30].C(N(CC)CC)C>C(O)C>[ClH:22].[CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]2[S:25][CH:28]=[C:29]([CH3:30])[N:26]=2)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncc(Oc3ccccc3Cl)cc2OCc2ccccc2)n1
Product: Cl

Procedure:
A mixture of 1-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-yl)thiourea (0.280 g, 0.660 mmol), 1-chloropropan-2-one (0.0733 g, 0.792 mmol), triethylamine (0.161 ml, 1.16 mmol), and ethanol (10 mL) was heated at reflux overnight. The reaction mixture was cooled and partitioned between ethyl acetate:ether (1:1) and water. The organic layer was washed with water, brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate to afford a free base of the title compound as a light yellow oil. The oil was dissolved in ether (6 mL), and 1M HCl in ether (2 mL) was added. The mixture was sonicated to break up the white solid. Hexanes (5 mL) were added, and the mixture was sonicated and filtered. The solids were washed with hexanes and dried to provide 3-(benzyloxy)-5-(2-chlorophenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.215 g, 70.7% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.31 (s, 3H), 5.33 (s, 2H), 6.82 (s, 1H), 7.01 (d, 1H), 7.22 (t, 1H), 7.32-7.43 (m, 5H), 7.51-7.62 (m, 5H), 7.67 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11][C:12]([CH3:14])=O.Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:11]([C:10]([O:16][CH3:17])=[O:15])=[C:12]([CH3:14])[NH:22][C:19]([CH3:20])=[N:21]1
Reactant: CC(=N)N
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=NC1c1ccccc1Cl

Procedure:
8.42 g (60 mmols) of 2-chlorobenzaldehyde are boiled with 6.48 ml (60 mmols) of methyl acetoacetate, 6.72 g (60 mmols) of acetamidine HCl and 5.91 g (72 mmols) of anhydrous sodium acetate in 180 ml of ethanol for 18 hours. The mixture is cooled and concentrated. 100 ml of 1N hydrochloric acid and ethyl acetate are added to the resulting evaporation residue and the mixture is shaken thoroughly. The mixture is left to separate, the ethyl acetate phase is extracted by shaking with 100 ml of 1 N hydrochloric acid and the combined aqueous phases are extracted once by shaking with ether and left to separate. The aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and extracted twice by shaking with ethyl acetate. The combined ethyl acetate phases are washed with water, dried and concentrated. The crystalline evaporation residue is recrystallized from acetonitrile. 2.5 g of a slightly yellow substance of melting point 225°-27° C. are obtained.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([C:13](=[O:34])[C:14](=[C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26]2)[C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)[OH:6])=[N+]=[N-].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([C:13](=[O:34])[C:14](=[C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26]2)[C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Yield: 47 %

Procedure:
A 568 mg portion of 1-[3-(2-azido-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione and 120 mg of 10% palladium-carbon were added to 50 ml of ethyl acetate and stirred at room temperature for 8.5 hours under ordinary pressure and in an atmosphere of hydrogen. This was filtered through celite, concentrated, mixed with diethyl ether and then extracted with water. By concentrating the water layer, 250 mg (47%) of 1-[3-(2-amino-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione (Example 14-1) was obtained as a yellow solid. FA: 436
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:41])[NH:16][C:15]1[CH:17]=[CH:18][C:12]([O:11][C:10]2[CH:20]=[CH:21][C:22]([CH2:24][CH3:25])=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:19])[CH:14]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCOC(=O)Cl
Product: CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)c(OCc2ccccc2)c1
Yield: 107.8 %

Procedure:
According to the procedure of example 44 (a) except substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (200 mg; 0.59 mmol) and ethylchloroformate by benzylchloroformate (150 μL; 0.73 mmol), the title compound (300 mg; quantitative) was prepared as a brown solid and used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].CS(O[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH3:22])(=O)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:21]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH2:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: C=C(c1ccc([N+](=O)[O-])cc1)N(c1ccc(C#N)cc1)c1cncnc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 1-(4-nitrophenyl)ethyl methanesulfonate
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1>CC(O)CCC>[ClH:2].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:27]([F:32])[CH:26]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCCN1CCCC1
Yield: 44.3 %

Procedure:
Using an analogous procedure to that described for Example 15, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (236 mg, 0.6 mmol), (prepared as described for the starting material in Example 31), was reacted with 4-chloro-2-fluoroaniline (80 μl, 0.72 mmol) in 2-pentanol (5 ml) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (124 mg, 42%).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:3]=1.C(N(CC)CC)C.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[CH:37]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:4]2[N:3]=[C:2]([C:37]#[C:36][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:6]([CH2:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])[N:5]=2)=[CH:23][CH:24]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1Br)N1CCN(c2ccccn2)CC1
Reactant: C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1C#Cc1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
20 mg triphenylphosphinpalladium(II)chloride and 5 mg cupper(I)iodide were added to 100 mg 2-(5-bromo-3-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone, 250 μl triethylamine and 45 mg ethynyl-benzene acid in 5 mL tetrahydrofuran. The reaction was stirred 2 h at 70° C. The reaction was filltered and evaporated. The residue was purified by HPLC to give 5 mg desired product. Rt: 1.24 min (method B), (M+H)+: 467
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].S1C=C[CH:10]=[C:9]1[Cl:13]>C(O)C>[ClH:13].[CH2:9]([O:4][C:3](=[O:5])[C:2]([NH2:1])([CH3:7])[CH3:6])[CH3:10]
Reactant: Clc1cccs1
Reactant: CC(C)(N)C(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)N
Product: Cl
Temperature: 5.400000095367432 °C
Reaction time: 5 h

Procedure:
Ethanol (400 L) was added to 2-aminoisobutyric acid (22.0 Kg). Thienyl chloride (30 Kg) was added to the mixture, maintaining the temperature at 5.40° C. The mixture was heated to reflux and stirred for a period of 4 to 6 hours. The reaction mixture was cooled to 5.40° C. The contents were distilled under atmospheric pressure to a residual volume of approximately 100 L.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]#N.[OH-:13].[Na+].[OH2:15]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:15])=[O:13]
Reactant: [OH-]
Reactant: COc1ccc(F)c(CC#N)c1
Reactant: O
Agent: [Na+]
Product: COc1ccc(F)c(CC(=O)O)c1

Procedure:
The solution of 2-(2-fluoro-5-methoxyphenyl)acetonitrile (200 mg, 1.0 mmol) and sodium hydroxide (81.5 mg, 2.0 mmol) in water was stirred at 100 degree for 8 h. The reaction mixture was evaporated under reduced pressure to get the crude product for the next step without further purification. LC-MS: m/z (M−H)=183.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:17])[CH3:16])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[OH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](O)=[O:23]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH:17][C:22](=[O:23])[CH:21]([OH:20])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:16])[N:10]=[CH:9]1)([CH3:7])[CH3:6]
Reactant: COC(=O)CC(C)(C)n1cnc(NC(=O)C(C)N)c1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Product: COC(=O)CC(C)(C)n1cnc(NC(=O)C(C)NC(=O)C(O)C(C)(C)C)c1

Procedure:
3-[4-(2-Amino-propionylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 19.2, 26.2, 28.1, 28.2, 35.2, 47.1, 48.6, 51.9, 56.4, 79.7, 105.1, 112.4, 131.0, 137.7, 169.7, 170.0, 173.0; MS 383.3 m/z (M+1).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([NH:23][C@@H:19]([CH2:18][CH:15]3[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]3)[C:20]([NH:34][CH2:33][CH2:32][NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:22])=[N:6][C:5]=2[CH:7]=1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: NCCNc1ccc(F)cc1
Reactant: Clc1ccc2oc(Cl)nc2c1
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared from 2,5-dichlorobenzooxazole, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.35 (d, 1H, J=8 Hz), 8.18 (t, 1H, J=5.8 Hz), 7.30 (d, 1H, J=8.4 Hz), 7.18 (d, 1H, J=2.0 Hz), 6.90 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 6.84(m, 2H), 6.51(m, 2H), 4.19(m, 1H), 3.15(m, 2H), 2.98(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28ClFN4O2(M+H+) 459.19, found 459.4.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH2:14])(=[O:13])=[O:12].C1([O:21][C:22](=O)[NH:23][C:24]2[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH3:32])[N:25]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:14][C:22]([NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH3:32])[N:25]=1)=[O:21])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1sccc1C1OCCO1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2sccc2C2OCCO2)n1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To 0.47 g of 3-(1,3-dioxolan-2-yl)thiophene-2-sulfonamide in 20 ml of acetonitrile was added 0.52 g of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After stirring at ambient temperatures for two hours the solution was diluted to 50 ml with water and the pH was adjusted to 3 by the addition of hydrochloride acid. The resultant solution was extracted with methylene chloride and the methylene chloride phase was dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with butyl chloride yielded 0.6 g of the product, m.p. 164°-166°. Infrared absorption spectra showed peaks at 1700, 1600 and 1550 cm-1, consistent for the desired structure. ##STR27##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[NH:6][CH:7]=[C:8]1[C:13](=[O:14])OC(C)(C)OC1=O.C(=O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:18]([C:13](=[O:14])[CH:8]=[CH:7][NH:6]2)=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Agent: O=C=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc2c(=O)cc[nH]c2cc1OC
Temperature: 185 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
5-((3-Methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 29.8 mmol) was suspended in DOWTHERM A, (trade mark of Fluka Chemie AG), (125 ml) and heated to 180-190° C. over 30 minutes. The starting material dissolved at 100° C. and carbon dioxide came off at approximately 180° C. The heating was stopped after a further 30 minutes and the product precipitated out as the temperature dropped. Upon reaching 40° C. ether was added and the mixture was stirred for 30 minutes. The solid was collected by filtration, washed with ether and dried under vacuum to give 7-methoxy-6-methoxycarbonyl-1,4-dihydroquinolin-4-one (5.56 g, 80%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].[CH:15]([NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23](Br)[N:22]=1)=[O:20])([CH3:17])[CH3:16]>CN(C=O)C.C(OCC)(=O)C.[Cu](Cl)Cl>[CH:15]([NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:11])([F:1])[F:12])[CH:5]=2)[N:22]=1)=[O:20])([CH3:17])[CH3:16]
Reactant: COc1cc(Br)nc(C(=O)NC(C)C)c1
Reactant: Oc1cccc(SC(F)(F)F)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(SC(F)(F)F)c2)nc(C(=O)NC(C)C)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
1.25 g (0.0029×2.2 mol) of 3-(trifluoromethylthio) phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.23 g (ca. 60% in mineral oil; 0.0029×2.0 mol) of NaH and then with 0.80 g (0.0029 mol) of N-(i-propyl)-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.15 g (0.0029×0.5 mol) of copper chloride (I), the obtained solution was stirred at about 110° C. for about 6 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#N.[OH-:13].[K+].[OH2:15]>C(O)C.CCOCC>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:1]([OH:15])=[O:13])[C:6]=2[CH:7]=1
Reactant: COc1ccc2c(c1)C(C#N)C2
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2c(c1)C(C(=O)O)=C2
Temperature: 25 °C

Procedure:
1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOH in ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60 ml) is added to the reaction mixture which is refluxed for about 3 hours. The mixture is cooled to RT, diluted with water, washed with ether and the aqueous layer acidified forming an oil. The oil is dissolved in ether and the ethereal solution washed, dried over Na2SO4, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].O.NN>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1cc([N+](=O)[O-])ccc1Br
Agent: NN
Solvent: CO
Solvent: O
Product: COCCOc1cc(N)ccc1Br
Temperature: 80 °C

Procedure:
An open 250 mL round bottom flask was charged with 1-bromo-2-(2-methoxyethoxy)-4-nitrobenzene (Method 10) (5 g, 18.11 mmol), 5 wt % FeCl3 on SiO2 (17.6 g, 5.43 mmol), activated carbon (10 g), and 100 mL MeOH. This resulting mixture was heated with stirring to 80° C. Hydrazine monohydrate (10.6 mL, 217 mmol) was then carefully added to the reaction mixture. After complete addition of the hydrazine monohydrate, the reaction mixture was stirred at 80° C. for an additional 40 min. The reaction was then allowed to cool to rt and filtered through a bed of Celite. The filter cake was washed with MeOH (˜150 mL) and EtOAc (˜150 mL). The resulting filtrate was conc in vacuo to give the title compound which was used without further purification (3.16 g, 71%) m/z: 247.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[NH:3]1.[H-].[Na+].[CH3:23]I>CN(C)C=O.O>[CH3:23][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]21[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]=[N:19][CH:20]=[C:13]21
Reactant: N#Cc1ccc2c(c1)C(=O)NC21CCCn2cncc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2cc(C#N)ccc2C12CCCn1cncc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 mmol of 3′-oxo-2′,3′,6,7-tetrahydro-5H-spiro[imidazo[1,5-a]pyridine-8,1′-isoindole]-5′-carbonitrile (Example 13) in 5 ml of N,N-dimethylformamide is treated with 1.2 mmol of sodium hydride (60% dispersion in oil). The reaction mixture is stirred for 20 minutes at room temperature, and then 1.2 mmol of methyl iodide are added. The reaction mixture is stirred for 20 minutes at room temperature, then diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12]Cl)[N:3]=1.[CH3:14][N:15]1[C:23]2[N:22]=[C:21](Br)[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:19]=2[C:18](=[O:33])[NH:17][C:16]1=[O:34].[C:35]([O:39][C:40]([NH:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:17]2[C:18](=[O:33])[C:19]3[N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:21]([N:45]4[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:44]4)=[N:22][C:23]=3[N:15]([CH3:14])[C:16]2=[O:34])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(CCl)nc2ccccc12
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Cl
Product: Cc1nc(Cn2c(=O)c3c(nc(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3Cc3ccccc3Cl)n(C)c2=O)nc2ccccc12

Procedure:
Prepared by reacting (4-methyl-quinazolin-2-yl)-methylchloride and 3-methyl-7-(2-chlorobenzyl)-8-bromo-xanthine and subsequently reacting with (R)-3-(tert.-butyloxycarbonylamino)-piperidine