Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH2:33][OH:34])[CH2:16][O:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])=[CH:21][CH:22]=2)=[N:13]1.C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]1([CH:33]=[O:34])[CH2:16][O:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])=[CH:21][CH:22]=2)=[N:13]1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC(C)(CO)CO2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC1CCCN1CCCOc1ccc(C2=NC(C)(C=O)CO2)cn1
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of oxalyl chloride (0.38 ml, 4.32 mmol) in dichloromethane (30 ml) is cooled to −78° C. and is treated slowly with dimethylsulfoxide (0.51 ml, 7.2 mmol). After 20 min at −78° C., a solution of (4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazol-4-yl)methanol ax56 (1.2 g, 80% purity, ca. 3.0 mmol) in dichloromethane (10 ml) is added dropwise over 10 min. After 60 min at −78° C., triethylamine (2.5 ml, 18 mmol) is added and the mixture is allowed to warm to 22° C. Water is then added and after vigorous stirring, the organic layer is separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated in vacuo to yield 1.2 g of ca. 80% pure 4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazole-4-carbaldehyde ax57.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:8][CH2:9][CH:10]3[CH2:15][O:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N+:8]([O-:31])[CH2:9][CH:10]3[CH2:15][O:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)N1CCOCC1CN=C2c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)N1CCOCC1C[N+]([O-])=C2c1ccco1
Yield: 36.4 %

Procedure:
A solution of 6 g of 1,2,4,4a-tetrahydro-10-methoxy-7-(2furyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine (for the preparation, see Example 2) in 100 ml of methylene chloride is heated under reflux with 4.2 g of 3-chloroperbenzoic acid for 3 hours. The reaction solution is then rendered alkaline with aqueous dilute sodium hydroxide solution and is worked up in the customary manner. The crude product isolated is purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and is crystallised from isopropanol. 2.3 g of 1,2,4,4a-tetrahydro-10-methoxy-7-(2-furyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine 6-oxide are obtained. Melting point: 183° to 186° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][CH2:14][C:15](=O)[CH3:16])[CH:6]=1)[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:15]=2[CH3:16])[CH:6]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(OC)c(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: 4-methoxy-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:11]([N:18]1[CH:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:7][CH:2]1[NH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1ccc(Cl)nc1
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)C1=CN(Cc2ccccc2)C(N)C=C1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
Dissolve 2-chloro-5-isopropylpyridine (5 g, 0.032 mol), benzylamine (6.8 g, 0.064 mol), Biphenyl-2-yl-dicyclohexyl-phosphine (0.46 g, 1.3 mmol), Pd(OAc)2 (0.14 g, 0.64 mmol), and sodium tert-butoxide (4.3 g, 0.045 mol) in 60 mL of toluene. Deoxygenate three times. Heat at 100° C. for 18 hours. Cool and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate to provide 5.5 g of the desired compound.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:27][NH:28][S:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:31])=[O:30]>>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][S:29]([N:28]([C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH3:27])(=[O:31])=[O:30])=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: CNS(=O)(=O)CCCCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared in a similar fashion as described in Example 2.1, starting from methyl 5-bromo-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 12; 10.3 mmol) and tert-butyl 4-(N-methylsulfamoyl)butylcarbamate (Example 8) to obtain the target compound (3.43 gr).
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[CH:1]1([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:50][CH2:51][C:52]3[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=3[CH3:58])=[O:16])=[CH:17][CH:18]=2)[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(OC1CCCCC1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)OC3CCCCC3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.6 %

Procedure:
To the solution of 4-(1-(cyclohexyloxy)ethyl)benzoic acid (62 mg, 0.25 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (143 mg, 0.38 mmol) and triethylamine (76 mg, 0.75 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (131 mg, 0.86 mmol) was added, the solution was stirred at room temperature for 12 hours, then washed with water (50 mL*3), the organic layer was evaporate ed and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give 4-(1-(cyclohexyloxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (57 mg, 60%). LRMS (M+H+) m/z: calcd: 382.23. found 382; 1H-NMR (300 MHz, CD3OD) δ 7.76 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.11 (s, 1H), 4.69-4.67 (m, 1H), 4.49 (s, 2H), 3.20-3.14 (m, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 1.69 (m. 1H), 1.51-1.49 (m, 3H), 1.38-1.36 (m, 1H), 1.29-1.20 (m, 8H).
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:11](Br)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C(C)=CC=CC=1>[C:1]([N:9]1[CH2:13][C@@H:12]2[C@@H:11]([N:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:15][O:14]2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CN(C(=O)c3ccccc3)C[C@H]2Br)cc1
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)N1C[C@H]2OCCN(Cc3ccccc3)[C@H]2C1

Procedure:
124 g (0.265 mol) of trans-1-benzoyl-3-bromo-4-(2-tosyloxyethoxy)-pyrrolidine are re-fluxed overnight with 86 g (0.8 mol) of benzylamine in 1.5 l of xylene. The benzylamine salts are suctioned off and the filtrate concentrated.
Reaction SMILES: [NH2:1][C:2]([CH3:30])([CH3:29])[CH2:3][NH:4][C:5](=[O:28])[NH:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:9][C:8]=1[F:27].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]([CH3:30])([CH3:29])[CH2:3][NH:4][C:5]([NH:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:9][C:8]=1[F:27])=[O:28]
Reactant: CC(C)(N)CNC(=O)Nc1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)CNC(=O)Nc1ccc(CC2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
tert-Butyl 4-(4-(3-(2-amino-2-methylpropyl)ureido)-3-fluorobenzyl)piperidine-1-carboxylate (2.272 mmol, 960 mg) was dissolved in dichloromethane (40 mL) and trifluoroacetic acid (45.4 mmol, 5181 mg) added. The mixture was stirred at room temperature for 3 hours before concentrating under reduced pressure. The resulting residue was purified by strong cation exchange column chromatography to afford the title compound (110 mg). MS (ESI) m/z 323.5 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:27])(=[O:26])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][CH:22]([NH:29][CH2:30][C@H:31]([OH:32])[C:33]4[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)(=[O:26])=[O:27])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid ethyl ester (which was obtained in Example 235) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.32 (t, J=7.1 Hz, 3 H), 1.75–1.90 (m, 2 H), 2.50–2.70 (m, 5 H), 2.91 (s, 3 H), 3.40–3.55 (m, 2 H), 4.32 (q, J=7.1 Hz, 2 H), 4.47 (dd, J=8.1, 4.2 Hz, 1 H), 6.70–6.90 (m, 5 H), 6.99 (dd, J=8.3, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.79 (d, J=8.5 Hz, 2 H), 8.07 (d, J=8.5 Hz, 2 H); MS (ES) m/z: 633.3 (MH+); HRMS Calcd. for C29H37N4O8S2 (MH+): 633.2047. Found: 633.2013.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of 3-chloro-2-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-2H-indazole (217 g) in conc. sulfuric acid (1 kg) was cooled to 5° C., and 99% nitric acid (67 g) was dropwise added thereto at a temperature below about 10° C., followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was added to ice-water (10 kg), and the precipitated crystals were collected by filtration, washed and dried to give 3-chloro-2-(2,4-difluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (227 g). m.p., 117°-118° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH2:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[N:11][C:3]=2[C:2]([F:1])([F:13])[F:12])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1cccnc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ncc(C(F)(F)F)cc1Cl)c1cccnc1C(F)(F)F

Procedure:
A solution of 204 mg (1 mmol) of 2-trifluormethyl nicotinic acid, 200 mg (0.9 mmol) of 2-(3-chloro-5-trifluormethyl-pyridin-2-yl)-ethylamine and 620 mg (1.3 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 230 mg (1.8 mmol) N,N-Diisopropylethylamine in 8 ml methylene chloride is stirred for 20 h at room temperature.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15].S([O-])([O-])(=O)=O.C[N+](C)(C)C.C[N+](C)(C)C.S(=O)(=O)(O)O>ClCCl.C(=O)([O-])O.[Na+]>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 50.6 %

Procedure:
4.97 g of 4-cyanobenzoyl chloride, 3.45 g of L-proline and 0.73 g of tetramethylammonium sulphate in 300 ml of dichloromethane and 150 ml of 5% sodium hydrogen carbonate solution are stirred for 48 hours. The aqueous phase is acidified With 3N sulphuric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with saturated sodium chloride solution, dried and evaporated. Chromatography of the residue on silica gel (RP-18) using water gives 3.70 g of 1-(p-cyanobenzoyl)-L-proline. M.p. 80°-85° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([N:1]([S:31]([CH3:30])(=[O:33])=[O:32])[C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Yield: 131.4 %

Procedure:
To a mixture of 1.00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4 (1H,3H)-pyrimidinedione, 0.63 g of triethylamine and 10 ml of dichloromethane, 0.48 g of methanesulfonylchloride was added at a temperature of not more than 5° C. The resultant mixture was stirred overnight. After washing twice the reaction mixture with water, the reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dichloromethane was distilled off to obtain a crude product. The obtained product was washed with diisopropylether to obtain 1.36 g of the objective product as white crystals. m.p.: 282°~285° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:35](=[O:36])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CSc1nccc(C(=O)N(C)NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: c1ccncc1
Product: CSc1nccc(C(=O)N(C)N(C(=O)Cc2ccc(F)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred 0° C. solution of 4-[N′-Methyl-N′-(2-methylsulfanyl-pyrimidine-4-carbonyl)-hydrazino]-piperidine-1-carboxylic acid tert-butyl ester, 16, (19.8 g, 51.7 mmol) in pyridine (25 mL) is added (4-fluorophenyl)acetyl chloride (10 g, 57.9 mmol). The reaction mixture is slowly warmed to room temperature and then stirred for 2 hours. The reaction mixture is then concentrated in vacuo. Purification over silica (100% EtOAc) affords 42 g of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.80-8.70 (m, 1H), 7.40-7.32 (m, 1H), 7.29-7.18 (m, 2H), 7.07-6.94 (m, 2H), 4.24-4.10 (m, 3H), 3.82-3.59 (m, 2H), 3.33 (d, J=8.4 Hz, 3H), 2.88-2.67 (m, 2H), 2.60 (d, J=18.6 Hz, 3H), 1.96-1.92 (m, 2H), 1.70-1.65 (m, 2H), 1.48 (d, J=4.0 Hz, 9H); ESI/MS: 518.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.6 g, 14.2 mmol) in methanol (50 mL) and tetrahydrofuran (100 mL), 30% sodium hydroxide in water (30 mL) was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3.6 g, 69%) as a white solid: LC/MS m/e calcd for C22H26N2O3 (M+H)+: 367.46, observed: 367.1.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26](C)[C:27](N)=O)=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][CH:21]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CN(C(N)=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 140 °C
Yield: 30.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.200 g, 0.67 mmol), 1-(4-aminophenyl)-1-methylurea (0.220 g, 1.33 mmol) and cone. HCl (2 drops) in NMP (5 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 3 h. After this time, the reaction mixture was cooled, diluted with water (40 mL) and then saturated sodium bicarbonate was added until pH˜8. The resulting solid was isolated by filtration then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.071 g, 30%) as a colorless oil. MW=349.86. 1H NMR (CDCl3, 500 MHz) δ 7.83-7.80 (m, 1H), 7.68-7.63 (m, 1H), 7.28-7.26 (m, 2H), 7.10-7.06 (m, 2H), 6.85 (s, 1H), 6.67-6.62 (m, 2H), 5.55 (s, 1H), 3.76 (br s, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.87 (s, 3H), 2.81 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); ESI MS m/z 350 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:26][N:25]([CH3:27])[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:24]=1
Reactant: CN(C)c1nc(NC2CCN(Cc3ccccc3)CC2)nc2ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1nc(NC2CCNCC2)nc2ccccc12
Reaction time: 72 h
Yield: 98.4 %

Procedure:
To a solution of N2-(1-benzyl-piperidin-4-yl)-N4,N4-dimethyl-quinazoline-2,4-diamine (1.80 g, 4.98 mmol) in MeOH (18 mL) was added 20% Pd(OH)2 (360 mg). The mixture was stiffed at 50° C. under hydrogen atmosphere for 3 days, filtered through a pad of celite, and concentrated to give N4,N4-dimethyl-N2-piperidin-4-yl-quinazoline-2,4-diamine (1.33 g, 99%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N#N.[Li]CCCC.[CH2:39]=[O:40]>C1COCC1.CC(=O)OCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH2:39][OH:40])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A solution of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate (650 mg, 1.5 mmol) in THF (20 mL, dry) was cooled to −78° C. and protected with N2. Another solution of n-BuLi (1.5 M, 3 mL, ˜4.5 mmol) in THF was added to the above cooled solution during 5 min. The reaction mixture was stirred at −78° C. for 1 h, followed by the addition of paraformaldehyde (405 mg, 15.0 mmol) in one portion under −78° C. This solution was stirred at RT overnight. The reaction was quenched by saturated aqueous NH4Cl (50 mL) and water (50 mL), and extracted with EtOAc (50 mL*4). The combined organic layer were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE:EA (4:1) to obtain the title compound as a yellow thicky oil (300 mg, 44% yield). MS (ES+) C23H29FN4O5 requires: 460. found 461 [M+H]+; purity: 93% (UV214).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[S:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[S:7])[NH:10]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: O=C1NC(=S)CS1
Solvent: CO
Product: N=C1NC(=C2SC(=O)NC2=S)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 49.7 parts of 2-oxo-4-thioxothiazolidine in 990 parts of methanol there was added at 40° C. and under an atmosphere of nitrogen 54.3 parts of powdered 1,3-diiminoisoindoline. Initially, a thick slurry resulted. The reaction mixture was stirred at room temperature for two hours during which time the mixture gradually thinned. The mixture was then heated at reflux for approximately two hours and after cooling to 25° C., was filtered. The collected solid was washed with fresh methanol and dried in vacuo at 50° C. to obtain 1-imino-3-(2-oxo-4-thioxo-5-thiazolidinylidene)isoindoline as an orange powder melting at 267°-8° C. (dec.).