Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:4](C)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24](C)[CH:25]=O)=[CH:20][C:19]=3[CH3:28])[C:14](=[O:29])[N:13]([C:30]3[CH:35]=[CH:34][C:33]([N:36](C)[CH:37]=O)=[CH:32][C:31]=3[CH3:40])[C:12]2=[O:41])=[C:7]([CH3:42])[CH:6]=1)=O>O1CCOCC1>[CH3:2][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][C:19]=3[CH3:28])[C:14](=[O:29])[N:13]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][CH3:37])=[CH:32][C:31]=3[CH3:40])[C:12]2=[O:41])=[C:7]([CH3:42])[CH:6]=1
Reactant: Cc1cc(N(C)C=O)ccc1-n1c(=O)n(-c2ccc(N(C)C=O)cc2C)c(=O)n(-c2ccc(N(C)C=O)cc2C)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ccc(-n2c(=O)n(-c3ccc(NC)cc3C)c(=O)n(-c3ccc(NC)cc3C)c2=O)c(C)c1
Temperature: 25 °C

Procedure:
Dioxane (52 ml), HCl (52 ml, 6 M) and 5 (6.5 g, 11 mmol) were mixed in a 250 ml round-bottom flask to form a pale slurry. The reaction mixture was heated to reflux for 30 minutes under argon. The now yellow solution was allowed to cool to room temperature and solvents were then removed on a rotary evaporator. The orange residue was then dissolved in 500 ml H2O and neutralized with a solution of NaHCO3 (sat.) under vigorous stirring. The precipitate formed was filtered off and washed several times with H2O giving a pale solid (4.7 g, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([O:17][CH2:18]C)=[O:16])[C:13](=[O:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]3[CH2:31][CH2:32][C:33](=[O:34])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].O=C1N(C2C=CC=C(C(F)(F)F)C=2)C2CCC(=O)C=2[C@@H](C2C=CC(C#N)=C[C:57]=2[S:64](C)(=[O:66])=[O:65])N1.ClC(OC)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:14]([C:15]([O:17][CH3:18])=[O:16])[C:13](=[O:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]3[CH2:31][CH2:32][C:33](=[O:34])[C:10]2=3)=[C:5]([S:64]([CH3:57])(=[O:66])=[O:65])[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: COC(=O)Cl
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The title compound is prepared in analogy to ethyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (example 31, 110 mg, 0.23 mmol), using (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A) as starting material and substituting ethyl chloroformate with methyl chloroformate. Yield: 76 mg; ESI mass spectrum [M+H]+=534; Retention time HPLC: 1.01 min (Z018_S04).
Reaction SMILES: [C:1]([C:3]1[C:4]2([CH2:9][CH2:10][CH2:11][CH:12]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2)#[CH:2].S(=O)(=O)(O)[OH:14].[OH-].[Na+]>C(O)(=O)C>[CH2:8]1[C:4]2([CH2:9][CH2:10][CH2:11][CH:12]=[C:3]2[C:1](=[O:14])[CH3:2])[CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(O)O
Reactant: C#CC1=CCCCC12CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)C1=CCCCC12CCCC2
Temperature: 75 °C
Yield: 294.1 %

Procedure:
A mixture of 6-ethynylspiro[4.5]dec-6-ene (120 g, 0.748 mol) and sulfuric acid (11.6 g) in acetic acid (500 ml) was heated for 2 h at 75° C., poured into ice, treated with 2N aqueous NaOH (10 ml) and extracted twice with MTBE (150 ml). The combined organic phases were treated with 2N aqueous NaOH (pH>7), washed with water (400 ml), with a saturated aqueous solution of NaCl (400 ml), dried (MgSO4), and concentrated. Short-path Vigreux-distillation (0.08 mbar, head temperature: 85-90° C.) of the crude product (125 g) gave 1-(spiro[4.5]dec-6-en-6-yl)ethanone (62 g, 46%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([NH2:36])[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH:19]3[CH2:20][O:21][CH2:22]3)[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:35][C:30]1[C:29]([NH2:36])=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Nc1ccccc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Yield: 49.9 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-1-ylmethyl)-9H-purine (0.2 g, 0.49 mmol), benzene-1,2-diamine (0.106 g, 0.98 mmol), Xphos (0.047 g, 0.098 mmol), Pd2(dba)3 (0.022 g, 0.025 mmol) and Cs2CO3 (0.32 g, 0.98 mmol) in DMF (2 mL) was subjected to microwave irradiation at 150° C. for 30 min. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give N-[9-Methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine as yellow foam (0.117 g, 50%). LCMS (Method A): RT=2.14 min, [M+H]+ 479.2
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1
Reactant: O=Cc1ccncc1
Reactant: CCOC(=O)c1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccccc1NCc1ccncc1
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-aminobenzoate (4 g) and 4-pyridylformaldehyde (1.2 eq) and NaBH3CN (2 eq) in methanol stirred overnight. The solvent was evaporated, and EtOAc (100 ml) and H2O (100 ml) were added. The solution was extracted three times with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give ethyl 2-[(4-pyridylmethyl)-amino]benzoate. The above compound (400 mg) was stirred with acetyl chloride (1.2 eq) and DIEA (1.2 eq) in dichloromethane at RT for two hours. The solution was washed with H2O followed by brine, dried over Na2SO4 and evaporated to give ethyl 2-[N-(4-pyridyl-methyl)acetylamino]benzoate for next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)N1CCC(=NNC(=O)c2ccccc2)CC1
Yield: 81.5 %

Procedure:
20 g (0.142 mol) of 1-acetyl-4-piperidone were dissolved in 400 mL of absolute ethanol and 21.2 g (0.156 mol) of benzoylhydrazine were added. The resulting solution was refluxed for 6 hours under stirring. The solvent was then removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethylether and 30 g (83% yield) of the title compound were collected by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[CH:2].[CH3:12][OH:13]>O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)#[CH:2]
Reactant: CO
Reactant: C#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Then, a solution prepared by dissolving 24.7 g (0.15 mole) of 4-ethynylbenzoic acid chloride in 30 ml of tetrahydrofuran was added dropwise into 300 ml of methanol cooled in an ice bath. After the addition was completed, the reaction solution became turbid in 20 minutes. The reaction mixture was kept being stirred for 2 hours in the ice bath and then stirred at the room temperature for further 2 hours. The reaction mixture was filtered and dried and 21 g (the yield: 87%) of methyl 4-ethynylbenzoate was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C@@H:25]2[C@@H:30]3[CH2:31][C@@H:27]([CH:28]=[CH:29]3)[C@@H:26]2[C:32]([NH2:34])=[O:33])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to example 712. Product was isolated as a tan solid (0.034 g, 35%). Mp 117-120° C.; LCMS (m/e) 482 (M); 1H-NMR (DMSO, 400 MHz) δ 9.11 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.70 (d, 1H, J=7.83 Hz), 7.39-41 (d, 1H, J=8.59 Hz), 7.26 (s, 1H), 7.14 (s, 1H), 6.99-7.01 (d, 1H, J=8.59 Hz), 6.38-6.34 (m, 1H), 6.30-5.97 (m, 1H), 4.15 (t, 1H, J=7.33 Hz), 3.59 (s, 2H), 3.10-12 (q, 2H, J=7.33 Hz), 2.91 (s, 1H), 2.88 (s, 1H), 2.77 (s, 3H), 2.40 (m, 2H), 2.10-12 (d, 1H, J=8.59 Hz), 1.39-42 (d, 1H, J=9.10 Hz), 1.13-17 (t, 3H, J=6.57 Hz), 1.01-04 (t, 3H, J=6.82 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17](B(O)O)[CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:22])=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH:14]=1
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2C)cn1
Temperature: 25 °C

Procedure:
Methyl 5-bromopicolinate (5.0 g, 23.1 mmol), (5-chloro-2-methylphenyl)boronic acid (4.5 g, 26.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.3 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3]>[Ni].CC(N(C)C)=O>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=O
Agent: [Ni]
Solvent: CC(=O)N(C)C
Product: CC(C)=CCCC(C)CCO

Procedure:
Apparently, the hydrogenation in the presence of Raney nickel is slow (18% citral remaining after 61/2 hours) and accompanied by a substantial amount of DMA.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:15]1[CH:36]=[CH:35][CH:34]=[CH:33][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[C:25](=[O:32])[CH:26]=[C:27]([CH2:30][OH:31])[O:28][CH:29]=1)[CH2:13][CH3:14]>ClCCl.C(OCC)C>[O:32]=[C:25]1[C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]2[CH:33]=[CH:34][CH:35]=[CH:36][C:15]=2[CH2:12][CH2:13][CH3:14])=[CH:29][O:28][C:27]([CH:30]=[O:31])=[CH:26]1
Reactant: CCCc1ccccc1OCCCCCOc1coc(CO)cc1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1ccccc1OCCCCCOc1coc(C=O)cc1=O
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a stirred solution of 4.44 g (20.6 mmole) of pyridinium chlorochromate in 50 ml of dichloromethane was added 3.46 g (10 mmole) of the title alcohol of Example 4 dissolved in 50 ml of dichloromethane. The resulting slurry was stirred at room temperature for twenty-four hours, then diluted with 100 ml of diethyl ether. The insolubles were removed by decanting and the supernatant was concentrated in vacuo. Purification by column chromatography afforded 1.4 g of the title compound, m.p. 95°-96°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=O)[CH:13]=1>ClC1C=CC=CC=1Cl>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[N:1]1[C:16]([CH3:18])=[CH:17][C:12]([OH:11])=[CH:13][C:14]1=[O:15]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Nc1cc(CO)ccc1Cl
Solvent: Clc1ccccc1Cl
Product: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
3-amino-4-chloro-benzyl alcohol (8.0 g, 51.0 mmol) and 4-hydroxy-6-methyl-2-pyrone (6.4 g, 51.0 mmol) were taken up in 1,2-dichlorobenzene (50 ml). The mixture was plunged into a 165° C. oil bath where it stirred for 20 minutes. The reaction was cooled to room temperature and the reaction was worked up by washing with saturated NaHCO3 (aq.) and extracting impurities with ethyl acetate. The product remained in the aqueous layer. The basic aqueous layer was made acidic with concentrated HCl. The product was extracted from the acidic aqueous layer with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and the solvent removed in vacuo. The product was obtained as a yellow oil in a 26% yield and was carried through to the next step with no further purification. 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.26 Hz, 2H), 7.51 (dd, J=8.46, 2.22 Hz, 1H), 7.36 (d, J=2.01 Hz, 1H), 6.13 (br s, 1H), 5.84 (d, J=2.42 Hz, 1H), 4.68 (s, 2H), 1.97 (s, 3H); LC/MS, tr=0.25 minutes and 1.41 minutes (tautomer), (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 266 (M+H).
Reaction SMILES: C([N:4]1[CH2:25][CH2:24][C:7]2[N:8]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:7]3[CH2:24][CH2:25][NH:4][CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: C=CCN1CCc2c(c3cc(C)ccc3n2C=Cc2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2C=Cc2ccncc2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
2-Allyl-8-methyl-5-(2-(pyridin-4-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.151 mmol) was dissolved in DCM (2 mL), which was degassed with nitrogen for 15 min. To this was added Pd(PPh3)4 (4 mg, 0.002 mmol) followed by 1,3-dimethyl barbituric acid (71 mg, 0.454 mmol). The reaction mixture was again degassed by nitrogen for 15 min. The resultant mixture was stirred at RT for 1 h. DCM was evaporated in vacuo. EtOAc (20 mL) was added to reaction mixture and was washed with saturated potassium carbonate solution (3×1 mL). The organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo and purified by reverse phase HPLC to obtain 2 mg of 8-methyl-5-(2-(pyridin-4-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, Free base): δ (ppm): 8.45 (d, 2H), 8.0 (d, 1H), 7.7 (d, 1H), 7.58 (d, 2H), 7.3 (s, 1H), 7.19 (d, 1H), 6.8 (d, 1H), 4.29 (s, 2H), 3.42 (m, 2H), 3.2 (m, 2H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]([CH3:16])[C:12](=[O:15])[CH2:13][N:14]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]=2[N:11]([CH3:16])[C:12](=[O:15])[CH:13]([OH:30])[N:14]=1
Reactant: CCc1cc2c(s1)N(C)C(=O)CN=C2c1ccccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc2c(s1)N(C)C(=O)C(O)N=C2c1ccccc1Cl
Temperature: 25 °C
Yield: 41.3 %

Procedure:
5-(2-Chlorophenyl)-7-ethyl-1-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one (3 g) was dissolved in chloroform (60 ml) and m-chloroperbenzoic acid (4.3 g) was added thereto with stirring at room temperature. The mixture was further stirred for 8 hours. The reaction mixture was washed with 0.5N sodium hydroxide and water and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue obtained was dissolved in acetic anhydride (30 ml). The mixture was stirred while heating at 70° C. After cooling, the reaction mixture was poured into water and neutralized with sodium hydrogen-carbonate. After the mixture was extracted with ethyl acetate, the organic layer was washed with an aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (40 ml). A solution of sodium hydroxide (0.6 g) in water (10 ml) was added thereto at room temperature with stirring and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and water (50 ml) was added thereto. After the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 1.3 g of crude 5-(2-chlorophenyl)-7-ethyl-3-hydroxy-1-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one. This compound (0.7 g) was dissolved in toluene (20 ml) and 3-methylphenylisocyanate (0.31 g) was added thereto. The mixture was stirred for 2 days while heating at 90° C. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 0.25 g of (5-(2-chlorophenyl)-7-ethyl-1-methyl-oxo-1,3-dihydro-2H-thieno[2,3-e][1,4]-diazepin-3-yl)-N-(3-methylphenyl)carbamate having a melting point of 181°-182.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:19]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:19])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(F)cc1O
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to a mixture of 4-fluorosalicylic acid (5 g, 32.0 mmol) and oxalyl chloride (7.11 mL, 80.1 mmol) in THF (35 mL). The mixture was stirred for 2 hours then reduced in vacuo. The residue was dissolved in THF (20 mL) and added dropwise to concentrated ammonium hydroxide solution (30 mL) at 0° C. The reaction was stirred at RT for 20 hours and the THF removed in vacuo. The residue was acidified and a white solid was filtered off. The solid was dissolved in ethyl acetate (80 mL) and the solution washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a yellow solid (2.4 g).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]([F:26])([F:25])[S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O)(=[O:15])=[O:14].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([S:13]([C:12]([F:26])([F:11])[F:25])(=[O:14])=[O:15])[CH:17]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: N=C(NO)c1cccnc1
Agent: N
Product: O=S(=O)(c1cccc(-c2nc(-c3cccnc3)no2)c1)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure of Example 1 using N-hydroxynicotinimidamide (Aldrich) and the compound of Example 6B. 1H NMR (300 MHz, DMSO-d6) δ 7.73 (dd, J=4, 5.0 Hz, 1 H), 7.85 (t, J=8 Hz, 1 H), 8.13 (m, 1 H), 8.43 (m, 1 H) 8.5 (m, 1 H), 8.6 (m, 1 H), 8.92 (m, 1 H), 9.37 (m, 1 H) ppm; MS (DCI/NH3) m/z 356 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])=[C:18]([F:23])[CH:17]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F

Procedure:
To 3.5 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 100 mL of absolute ethanol was added 2.3 mL of 4-chloro-2-fluoroaniline. After stirring the reaction under an inert atmosphere for 24 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ethyl acetate/hexanes. Drying in vacuo yielded 1.9 (40%) of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile as yellow needles: melting point 249-252° C.; mass spectrum (m/e): M+H 316.9.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[C:21]1([N:16]([CH2:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(c2ccccc2)S(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)N(CC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methanolic hydrogen chloride (4M, 20 mL) was added to a stirred, cooled (0° C.) suspension N-[(1-t-butoxycarbonylpiperidin-4-yl)methyl]-N-phenylmethanesulfonamide (2.84 g, 7.7 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to give the title compound as a tan foam (2.34 g, 100%), δH (250 MHz, d6 -DMSO) 8.90 (2H, br m), 7.45-7.33 (5H, m), 3.53 (2H, d, J 7.0 Hz), 3.19 (2H, m), 2.96 (3H, s), 2.73 (2H, m), 1.80 (2H, m), 1.54 (1H, m), and 1.36 (2H, m).