Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:24][C@H:23]2[C@@H:19]1[CH2:20][N:21](C(OCC1C=CC=CC=1)=O)[CH2:22]2.[H][H]>CO.[Pd]>[C@@H:23]12[CH2:24][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:3]3[C:4]4[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=4[C:6](=[O:9])[CH2:7][CH2:8][C:2]3=[O:1])[C@H:19]1[CH2:20][NH:21][CH2:22]2
Reactant: [H][H]
Reactant: O=C1CCC(=O)N(CCCCN2C[C@@H]3CN(C(=O)OCc4ccccc4)C[C@@H]32)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: O=C1CCC(=O)N(CCCCN2C[C@H]3CNC[C@@H]32)c2ccccc21
Yield: 67.9 %

Procedure:
In the presence of Pd/C (0.01 g, 10%), benzyl (1R,5R)-6-[4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)butyl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate from Example 65 (0.45 mmol, 0.21 g) in methanol (7 ml) was reacted with hydrogen to obtain 0.10 g of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].[Li].[H-]>O>[C:2]1([CH:1]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][NH:21][CH2:18][CH2:19][NH:20]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: NCCN
Agent: [H-]
Agent: [Li]
Solvent: O
Product: c1ccc(C2NCCNCc3ccccc32)cc1

Procedure:
Add 40 g. of the condensation product of o-benzoylbenzoic acid and ethylenediamine in small portions to a suspension of 15 g. of lithium aliminum hydride in 1500 ml. of anhydrous either with stirring. Reflux with stirring for 16 hours. Cool and add water carefully to decompose excess hydride. Separate the ether layer, dry over magnesium sulfate, and remove the solvent under reduced pressure to obtain 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine, m.p. 125° C. To prepare the dihydrochloride, dissolve the base in anhydrous ether and saturate with dry hydrogen chloride. Separate the precipitated solid, and recrystallize from ethanol to obtain 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine dihydrochloride, m.p. 297° C. (dec.).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (83 mg, 90%), MS (ISP) m/z=370.4 [(M+H)+], mp 241.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:10]=2)[C:5]1=[O:20]>CC(O)=O>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[CH:10]=2)[C:5](=[O:20])[N:4]([CH3:3])[CH:13]=1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)ccc3c2)cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1

Procedure:
Bromine (1.8 g, 11.25 mmol) in HOAc (6 mL) was added to the title compound of 2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (3 g, 12.5 mmol) in HOAc (24 mL) at 0° C. The mixture was stirred at 30° C. for 15 min, quenched with H2O (100 mL), and the resulting yellow solid was collected by filtration to give the title compound (2.04 g, 56%). 1H NMR (CDCl3, 400 MHz) δ 8.42 (d, J=8.4 Hz, 1H), 7.87 (d, J=28.8 Hz, 2H), 7.82 (d, J=15.6 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 7.38 (s, 1H), 4.00 (s, 3H), 3.61 (s, 3H). LCMS: 318.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@@H:10]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@@H:10]([CH2:32][C:33]([OH:35])=[O:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round-bottomed flask with tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetate (0.057 g, 0.099 mmol; Example 21, Step D) in DCM (1 mL) was added TFA (1.129 g, 9.90 mmol) at 0° C. The ice-bath was removed and the mixture was stirred at rt for 3h. The solvent was removed. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 10 to 90% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][NH:7][CH2:6][CH2:5]2
Reactant: O=C(N1CCc2cc(Cl)c(F)cc2C1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1cc2c(cc1Cl)CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 1-(6-chloro-7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (400 mg) in MeOH (15 mL) was added K2CO3 (572 mg, 4 mmol) in H2O (10 mL). The resulting reaction mixture was stirred at room temperature for 2 hours before it was acidified with HCl (1N) to pH 8. It was then extracted with EtOAc and the organic layer was washed with H2O (2×25 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo to tive the crude title product together with a regioisomer (170 mg). Prep-TLC separation (30% EtOAc in petroleum ether) then gave the desired title compound (130 mg) as a white solid.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=[C:3]([NH2:12])[CH:2]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])[C:17]([Cl:32])=[CH:16][N:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:32][C:17]1[C:18]([NH:20][C:21]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:19][C:14]([NH:12][C:3]2[CH:2]=[CH:1][C:6]3[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=3[CH:4]=2)=[N:15][CH:16]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)OCCCN2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3)ncc1Cl
Yield: 9.4 %

Procedure:
6,7,8,9-Tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (0.115 g, 0.700 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.243 g, 0.770 mmol), and 10-Camphorsulfonic acid (251 mg, 1.08 mmol) in Isopropyl alcohol (4.00 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was filtered and purified directly by HPLC to give enriched product, which was conc. and repurified. The fractions were concentrated and neutralized with MP-carbonate resin to afford 2-[5-Chloro-2-(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a yellow foam (29 mg, 9%). LCMS: 443; 1H-NMR (CDCl3): 8.65 (s, 1H), 8.04 (m, 2H), 7.45 (m, 1H), 7.30 (m, 3H), 7.12 (s, 1H), 6.82 (m, 1H), 6.69 (m, 1H), 6.55 (d, 1H, J=8.4 Hz), 6.10 (q, 1H, J=4.0 Hz), 4.00 (t, 2H, J=5.2 Hz), 3.15 (t, 2H, J=5.5 Hz), 2.91 (d, 3H, J=4.8 Hz), 1.98 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10](I)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([S:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:11]
Reactant: Fc1ccc(S)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc(F)c(F)c1
Reaction time: 2 h

Procedure:
A solution of 3,4-difluorothiophenol (3 g), ethyl iodide (1.6 ml), potassium carbonate (2.64 g) and DMF (40 ml) were charged to a flask and stirred for 2 h. The solution was partitioned between ethyl acetate and water. The organic extracts were dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound (3.84 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14]C1C=C(C(O)=O)C(O)=CC=1.O>C(O)(=O)C>[Cl:14][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([OH:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The following procedure demonstrates the preparation of compound 1 with X=5-Cl, with comparable procedures being useful for obtaining related compounds having different X substituents. A solution suspension of 10 g of 5-chlorosalicylic acid in 50 mL glacial acetic acid was cooled in an ice bath until the solvent began to freeze. The bath was exchanged to a room temperature water bath and 4.47 g of 90% fuming nitric acid (1:1 equivalent) in 3 mL glacial acetic acid was added dropwise. After addition was complete, the mixture was stirred for 150 minutes at room temperature (R.T.) in the water bath. It was then poured into 120 mL of ice and water and stirred in an ice bath for 30 minutes. The precipitated solid was collected by filtration and air-dried overnight.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[CH:9]1([NH:14][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCC1
Reactant: Nc1nccc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nccc(NC2CCCC2)n1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
A mixture of 2-amino-4-chloropyrimidine (22.8 g, 176 mmol), cyclopentylamine (20.9 mL, 211 mmol) and triethylamine (29.4 mL, 211 mmol) in EtOH (200 mL) was heated at reflux (105° C., oil bath) for 48 h. Upon workup, the volatile was removed in vacuo. The residue was poured into ice and saturated Na2CO3 aqueous solution and extracted with ethyl acetate (3×). The combined organics were washed with saturated Na2CO3 aqueous solution (1×), dried over Na2SO4, and concentrated in vacuo to give N4-cyclopentylpyrimidine-2,4-diamine (315) (26.5 g) as a light yellow solid of 92% purity. This batch of material was taken onto the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 179.1, Calculated 179.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Mg]Cl)(C)C.CON(C)[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=1.Cl>C1COCC1>[CH3:23][S:22][C:18]1[CH:17]=[C:16]([C:15]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[O:24])[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1cnnn1
Reactant: CON(C)C(=O)c1cccc(SC)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CSc1cccc(C(=O)c2nnnn2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (4.20 g, 50 mmol) in anhydrous THF (200 mL), cooled to 0° C. with a brine/ice bath, was added dropwise a solution of isopropylmagnesium chloride (2 M in THF, 30 mL, 60.2 mmol). After the addition was over, the resulting cloudy suspension was stirred for 15 min at 0° C. A solution of N-methoxy-N-methyl-3-(methylsulfanyl)benzamide (10.2 g, 39 mmol) in THF (80 mL) was then added dropwise while keeping the internal temperature below 5° C. The reaction mixture was then allowed to warm up and stirred overnight at room temperature. Aq. HCl (1 M, 65 mL) was added to the reaction mixture, the layers were separated, the water phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over MgSO4. Purification on silica gel afforded [3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone as a yellow solid [5.95 g, yield 43%; HPLC/MS: m/z=235 (M+H); logP(HCOOH)=2.52].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:14]2[C:19]=1[C:18](=[O:26])[CH2:17][CH2:16][CH2:15]2
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1ccc(N)c2c1CCCC2=O
Reaction time: 1.5 h
Yield: 109.3 %

Procedure:
5-[3'-(t-Butoxycarbonylamino)propyloxy]-8-nitro-1,2,3,4-tetrahydronaphthalen-1-one (3.55 g) is dissolved in ethanol (160 ml), and thereto is added 10% palladium-carbon (420 mg). The mixture is stirred under hydrogen atmosphere for 1.5 hour, and the catalyst is removed by filtration. The filtrate is concentrated, and the residue is purified by silica gel column chromatography to give the title compound (3.56 g) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27](=[O:30])[CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:26]([C:27](=[O:30])[CH2:28][CH3:29])[C@H:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH:5]=[CH:4][C:3]([OH:38])=[O:2])[CH:7]=3)[N:12]([C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([CH3:25])[CH2:10]2)=[CH:32][CH:33]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of (±)-cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid methyl ester (110 mg, 0.21 mmol) in 4 ml methanol was added 50 mg K2CO3, (0.36 mmol, in 2 ml water). The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed under vacuum. 1M HCl was added until the mixture was acidic. Dichloromethane (25 ml) was added. Organic layer was dried with magnesium sulfate. Dichloromethane was removed under vacuum. The residue was purified by HPLC to give 10 mg title compound
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[S:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)CCc1sc(Cl)nc1-c1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of methyl 3-(2-chloro-4-phenyl-5-thiazolyl)propionate (380 mg), 4-hydroxythiophenol (341 mg), potassium carbonate (373 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and-concentrated to give methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (464 mg, yield 93%) as colorless crystals. The crystals were recrystallized from toluene-hexane. melting point: 153–155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C1CCCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: COc1cccc2c1CCC2=O
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: COc1cccc2c1CCC2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of 9.38 g (0.057 mol) of 4-methoxy-1-indanone in 250 ml of ether cooled to 0° C. was added dropwise over 5 min 33.72 ml (0.0607 mol) of 1.8M phenyllithium in cyclohexane/ether and the mixture was stirred at room temperature for 1 h. An additional (10 ml) phenyllithium solution was added and stirred at room temperature for 1 h. To the reaction mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 14.3 g of crude 4-methoxy-1-phenyl-indan-1-ol which was used directly in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:21])[CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:9].[S:22](Cl)([Cl:25])(=[O:24])=[O:23]>C(Cl)Cl>[CH2:14]([N:13]([S:22]([Cl:25])(=[O:24])=[O:23])[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A solution of triethylamine (2.0 ml, 14.4 mmol) and N-benzylglycine ethyl ester (2.25 ml, 12.0 mmol) in methylene chloride (5 ml) was added to a solution of sulfuryl chloride (0.96 ml, 12.0 mmol) in methylene chloride (30 ml) at -78° C. The reaction mixture was stirred at -78° C. for 4 h and then concentrated. Ether (75 ml) was added and the resulting precipitate was filtered. The organic layer was washed with 1M HCl and brine, dried over MgSO4 and concentrated in vacuo to give ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate as a colorless oil (69%).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(O)C>[C:2]([NH:3][C:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1)=[S:16])#[N:1]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
The suspension of monosodium cyanamide (6.4 g, 100 mmol) in absolute ethanol (170 mL) was slowly treated with (4-nitrophenyl)isothiocyanate (12.5 mL, 104.5 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (13.6 g), m.p. >250° C.
Reaction SMILES: [NH2:1][C:2]([NH2:19])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8](Cl)=[CH:7][C:6]=1[CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].C[Si](C)(C)[O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]([NH2:19])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([N:32]2[CH:33]=[CH:34][C:29](=[O:28])[CH:30]=[CH:31]2)=[CH:7][C:6]=1[CH2:16][CH3:17]
Reactant: C[Si](C)(C)Oc1ccncc1
Reactant: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2ccc(=O)cc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
3 g of N-diaminomethylene-2-ethyl-4-chloro-5-methylsulfonylbenzamide [obtainable by reacting methyl 2-methyl-4-chloro-5-methylsulfonylbenzoate with guanidine] are heated with 30 ml of 4-trimethylsilyloxypyridine in the presence of 3 g of K2CO3 in a closed tube at 135° for five hours. The mixture is cooled, the excess silylpyridine is removed by decanting, and the residue is triturated with ether and filtered off with suction. The solid residue is then dissolved in methanol and chromatographed over silica gel (ethyl acetate/methanol). Recrystallization from isopropanol and ethanol gives N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulfonylbenzamide, m.p. 261-263°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[CH3:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.57 g, 76%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.60 g, 3.25 mmol) and 3-methylphthalic anhydride (0.79 g, 4.87 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:35])[N:29]=[C:30](SC)[NH:31][CH:32]=2)=[CH:22][N:21]=1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:30]3[NH:31][CH:32]=[C:27]([CH2:26][C:23]4[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=4)[C:28](=[O:35])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (0.216 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.108 mmol, 0.5 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.090 mmol; yield: 18%, HPLC-MS/UV: [M+H]+=448.34; rt: 10.25 min; purity: 94%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.88 (t, J=7.17, 2H), 3.51 (s, 2H), 3.55-3.67 (m, 2H), 3.95 (s, 3H), 5.11 (br.s., 1H), 6.87-7.05 (m, 5H), 7.14-7.21 (m, 2H), 7.23-7.30 (m, 1H), 7.65 (s, 1H), 8.39 (s, 1H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=[C:2]3[C:11]=2[CH:10]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(C)cc2c1Cl
Product: Cc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1

Procedure:
The title compound was prepared following the procedure described in Step 3 using 3f and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 2.46 (3H, s), 7.16 (1H, t, J=7.41 Hz), 7.41 (2H, dd, J=8.51, 7.14 Hz), 7.46 (1H, dd, J=8.52, 1.92 Hz), 7.58 (1H, d, J=8.51 Hz), 8.00 (1H, br), 8.21 (2H, dd, J=7.69, 1.10 Hz), 8.66 (1H, s). m/z 276.3 (MH+).