Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:19]=[N+:20]=[N-:21])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Temperature: 100 °C

Procedure:
To a solution of trans-2-(4-bromophenoxy)cyclopentyl methanesulfonate (3.52 g, 10.5 mmol) in dimethylformamide (22 mL) was added sodium azide (897 mg, 13.7 mmol) and the reaction was heated at 100° C. for 18 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and 1N aqueous lithium chloride solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo to provide product as a brown oil, which was used in the next step without additional purification. Yield: 2.59 g, 9.18 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 1.65-1.73 (m, 1H), 1.89-2.05 (m, 5H), 3.74 (m, 1H), 4.66 (m, 1H), 6.83 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]3[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]3[CH:26]3[CH2:28][CH2:27]3)=[CH:18][C:17]=2[F:33])[CH2:12]1)[CH3:10])=O)(C)(C)C.Cl>C(O)C>[NH2:8][CH:9]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]3[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]3[CH:26]3[CH2:27][CH2:28]3)=[CH:18][C:17]=2[F:33])[CH2:12]1)[CH3:10]
Reactant: CC(NC(=O)OC(C)(C)C)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Agent: Cl
Solvent: CCO
Product: CC(N)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C

Procedure:
7-[3-(1-(N-tert-butoxycarbonylamino)ethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4 -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid isomer A (0.78 g, 0.0017 mole), preformed above, in ethanol (37 mL)/1N HCl (15 mL) was heated at 90° for 75 minutes. The reaction was cooled to room temperature and the solvent partially removed under reduced pressure. On standing a solid formed. This was filtered, washed with ethanol/diethyl ether, and then with diethyl ether and was dried in an oven under vacuum at 70° for two hours to give 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid isomer A (0.40 g, 57%) as a white powder, mp 322°-325° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:13][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NCc1ccc(Br)cc1
Yield: 76.7 %

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (2.0 g, 8.0 mmol), isopropylamine (950 mg, 16 mmol) and potassium carbonate (2.2 g, 16 mmol) in acetonitrile (40 mL) was stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, 0-100% methylene chloride/methanol) to afford the desired product (1.4 g, 78%) as a brown solid: ESI MS m/z 228 [C10H14BrN+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH3:11]CCCC.C(OCC)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:6][CH2:11]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CCCCC
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: CCOCC
Product: Fc1cc(F)cc(C2CO2)c1

Procedure:
Following General Procedure EC and using 3,5-difluorobenzaldehyde (Aldrich), the title compound was isolated after flash chromatography with 20:1 pentane/diethylether.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:13][C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[Br:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCCN2CCOCC2)c1
Temperature: 80 °C
Yield: 45.6 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.12 mmol), potassium carbonate (2.5 g, 18.37 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.4 g, 7.35 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated to an oil. Purification by column chromatography on silica gel using 0-50% EtOAc/hexane as eluent gave the product (1.0 g, 47%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:29][C@H:30]1[CH2:31][O:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=[N+]([O-])c1ccc(O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A 500 mL round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar is charged with: 2-(benzyloxy)-4-nitrophenol (10.00 g, 40.8 mmol), potassium carbonate (7.05 g, 51.0 mmol), (R)-(−)-glycidyl tosylate (10.00 g, 43.8 mmol) and DMF (65 mL). The mixture is immersed in an oil bath heated to 60° C. and stirred for 18 h. The solution is allowed to cool to rt, then water (200 mL) is slowly added. The resulting suspension is stirred for 2 h, the precipitate is collected by vacuum filtration and the filter cake is washed with water (25 mL). The cake is dried under suction to yield 10.70 g (87%) of the title compound as a light yellow powder. LCMS (Standard Method): 2.74 min, 302 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.48-7.34 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 4.43 (dd, J=2.7, 11.5 Hz, 1H), 4.08 (dd, J=5.8, 11.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.95-2.91 (m, 1H), 2.81-2.78 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[N:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2C(F)(F)F)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2ccccc2C(F)(F)F)n1
Yield: 28 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(2-trifluoromethyl-phenyl)-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (28% yield). 1H NMR (DMSO-d6) δ 6.06 (s, 1H, Ar), 6.45 (s, 2H, NH2), 7.32 (d, 2H, J=8.9 Hz, Ar), 7.49 (d, 1H, J=9.0 Hz, Ar), 7.62-7.75 (m, 2H, Ar), 7.81 (d, 3H, J=8.9 Hz, Ar), 9.37 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[OH-].[NH4+:21]>>[Br:1][C:2]1[C:10]2[C:9]([NH2:21])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1c(Br)cn2CCN1CCOCC1
Agent: [OH-]
Product: Nc1ncnc2c1c(Br)cn2CCN1CCOCC1
Temperature: 100 °C
Yield: 68 %

Procedure:
To 5-bromo-4-chloro-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (240 mg, 0.694 mmol) in a 5 mL sealable vial was added ammonium hydroxide (1.5 mL, 38.5 mmol). The reaction vial was capped and heated at 100° C. overnight. The reaction was cooled and solid formed. The solid was isolated by filtration and the solid was washed with NH4OH. The solid was air dried to isolated the desired product 5-bromo-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154 mg, 68.0% yield) as an off white solid. LC-MS (ES) m/z=326.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 8.10 (s, 1H), 7.47 (s, 1H), 6.69 (br. s., 2H), 4.22 (t, J=6.44 Hz, 2H), 3.52 (t, J=4.42 Hz, 4H), 2.65 (t, J=6.44 Hz, 2H), 2.41 (d, J=4.04 Hz, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)O)ccc21
Yield: 111.2 %

Procedure:
The benzyl 1-t-butoxycarbonylmethyl-1H-indole-5-carboxylate (800 mg) obtained above was dissolved in ethanol, then 5% palladium on carbon (160 mg) was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (670 mg, Y.:quant.).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH:28][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:32][CH:33]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCc1cccc(COc2ccc(Cl)cc2)c1
Product: O=c1c(NCc2cccc(COc3ccc(Cl)cc3)c2)c(Nc2cccnc2)c1=O
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 3-(4-chlorophenoxy-methyl)-benzylamine.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH:10]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCCC(CC=Cc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1CCCCC(CCCc2ccccc2)N1

Procedure:
The title material of Example 32 (0.46 g, 2.0 mmol) in MeOH and 4% Pd on carbon (0.10 g) were combined in a standard Parr apparatus (125 mL bottle). The hydrogenation was carried out at room temperature under a H2 pressure of 5 psi for 1 hr. All solvent was then removed under reduced pressure to yield 0.50 (09%) of the title material as a white semi-solid.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([CH:18]=O)=O>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:18]=[C:16]([C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[F:8])[N:4]=1
Reactant: O=CC(=O)c1ccc(F)cc1F
Reactant: CSC(=N)NN
Solvent: O
Product: CSc1nncc(-c2ccc(F)cc2F)n1
Yield: 69.7 %

Procedure:
3-(Methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00 g, 78%) was prepared from methyl hydrazinecarbimidothioate (0.63 g, 6.0 mmol) and 2,4-difluorophenylglyoxal monohydrate (1.00 g, 6.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]S(C)(=O)=O)[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:25]=[N+:26]=[N-:27])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)n1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Yield: 79.3 %

Procedure:
(5R)-3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-[(methanesulfonyl)methyl]-oxazolidin-2-one (Intermediate 24a) (5.432 g, 14.7 mmol), sodium azide (1.092 g, 16.6 mmol), and 18-crown-6 (0.069 g, 0.26 mmol) in dimethylformamide (15 mL) were heated to 90° C. for 3.75 hours. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined organic layers were washed once with brine, dried over MgSO4 and concentrated under vacuum. Chromatography on silica gel with 5% methanol in dichloromethane gave the title compound (3.7 g) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>C(Cl)Cl>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-(4-[2-(methoxycarbonylamino)-phenyl]-piperidyl}-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (412 mg, 0.61 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound as a white foam (159 mg). MS (ESI, pos. ion) m/z: 575 (M+1); (ESI, neg. ion) m/z: 573 (M−1). Calc'd for C32H35ClN4O4: 574.23. Anal. Calcd for C32H35ClN4O4.18C2HF3O2: C, 57.45; H, 5.06; N, 7.75. Found: C, 57.66; H, 5.09; N, 7.62.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)CC)C.Cl[C:18]([C:20]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21]1)=[O:19]>O1CCCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:20]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(=O)C1(C(=O)Cl)CCC1
Reactant: Cc1cc(Br)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Into a nitrogen-purged reaction flask was charged 2.74 grams (0.01 mole) of 4-bromo-2-methylaniline and 1.49 grams (0.0) mole) of triethylamine dissolved in 200 milliliters of tetrahydrofuran. With vigorous stirring, 2.80 grams (0.01 mole) of ethyl 1-chlorocarbonylcyclobutanecarboxylate prepared in Example XIX were added and the resulting mixture stirred at ambient temperature for 6 hours. A precipitate of triethylamine hydrochloride was removed by filtration. The filtrate was vacuum stripped and the residue taken up in methylene chloride. This solution was washed successively with 2N HCl (2×75 milliliters) and water, and then dried over magnesium sulfate. Rotary evaporation gave a crude product which was flash chromatographed on silica using 7:3 hexane-ethyl acetate to give 3.68 grams (0.01 mole) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclobutanecarboxylate as a white solid. A small sample which was recrystallized from hexane had a melting point of 61° C.-64° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12].C(N(CC)CC)C.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23])[CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C1NCCNC1c1cccs1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)N1CCNC(=O)C1c1cccs1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
9.1 g (0.05 mol) of 3-(2-thienyl)-piperazin-2-one, prepared in accordance with Example 16, are mixed with a solution of 6.1 g (0.06 mol) of triethylamine in 100 ml of chloroform, and 8.6 g (0.06 mol) of dimethylaminosulphonyl chloride are added dropwise slowly. The reaction mixture is then stirred for a further 6 hours at room temperature and evaporated in vacuo, the residue is stirred with water and the mixture is extracted by shaking with ethyl acetate. The ethyl acetate phase is separated off, the ethyl acetate is removed by distillation and the residue is recrystallised from ethanol.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2.[Cl-].[Li+].O.Cl>CC(N(C)C)=O>[OH:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2cnc3cc(OC)cc(O)c3c2=O)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
A suspension of 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (2.40 g, 7.68 mmol), as prepared in Example 18 or 19 and anhydrous lithium chloride (6.51 g, 153.6 mmol) in anhydrous dimethylacetamide (51.2 mL) was warmed to 135° C. After 3 to 5 min the trimethoxy compound goes into solution, then after approximately 10 min a voluminous precipitate formed. The precipitate redissolved after 20 min and the resulting solution was stirred at 135° C. for an additional 2.5 h. Upon cooling to room temperature, the reaction was poured into water (100 mL) and acidified with 1.0N HCl which gave a white precipitate. The mixture was extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to remove the methylene chloride, leaving a white precipitate in dimethylacetamide. Filtration provided 1.10 g (48% yield) of 5-hydroxy-7-methoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone, as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Reactant: C1COCCN1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CN4CCOCC4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with morpholine. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.09 (s, 2H, CH2), 3.27-3.31 (m, 4H, CH2), 3.62-3.64 (m, 4H, CH2), 7.04 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.54 (d, 2H, J=8.8 Hz, Ph-H), 7.67 (d, 2H, J=8.8 Hz, Ph-H), 8.48 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 9.59 (s, 1H, NH). MS (ESI+) m/z 425.01 [M+H]+ (C21H24N6O2S requires 424.52).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=1)([CH3:21])[CH3:22]
Reactant: CSc1ccc(CNc2ccc(C(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CSc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cc1
Yield: 82.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-isopropylphenyl)[(4-methylthiophenyl)methyl]amine (2.0 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(4-methylthiophenyl)methyl]urea (2.9 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[N:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][N:11]=2)[C:3]1=[O:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:17]#[C:16][C:13]2[CH:14]=[CH:15][C:10]([N:4]3[CH:5]4[CH2:9][CH2:8][CH2:7][CH:6]4[N:2]([CH3:1])[C:3]3=[O:22])=[N:11][CH:12]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN1C(=O)N(c2ccc(C#C[Si](C)(C)C)cn2)C2CCCC21
Reactant: Fc1cccc(I)c1
Product: CN1C(=O)N(c2ccc(C#Cc3cccc(F)c3)cn2)C2CCCC21

Procedure:
The title compound, a light yellow oil, MS: m/e=336.2 (M+H+), was prepared in accordance with the general method of Example 37, step 3 starting from (3aRS,6aSR)-1-methyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-hexahydro-cyclopenta-imidazol-2-one (Example 109, step 1) and 1-fluoro-3-iodobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].CN(P(N(C)C)(N(C)C)=O)C.[CH2:22](I)[CH:23]=[CH2:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:24][CH:23]=[CH2:22])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCOCC1
Reactant: C=CCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCOCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To this was added tetrahydro-pyran-4-carboxylic acid methyl ester (7.2 g, 50 mmol) in THF (10 mL). There was almost no color change (light a little bit). This was stirred at −78° C. for 45 min. Then, a mixture of 5 g of HMPA and 10.92 g of allyl iodide was added via canula. Towards 90% of addition, white precipitate formed suddenly. This mixture was stirred at −78° C. for 20 min, then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture to warm to r.t. over 30 min. When the precipitate was dissolved, the reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated; the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated in vacuo to get 8.75 g (95% yield) of the title compound as a yellow liquid.