Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl>[CH3:20][NH:21][C:22]([O:12][C@H:11]1[C@H:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:10]1)=[O:23]
Reactant: CN=C=O
Reactant: CN(C)C(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1CN(C(=O)N(C)C)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A solution of 1.0 g. (0.003 mole) of trans-3-(4-chlorophenoxy)-4-hydroxy-N,N-dimethyl-1-pyrrolidine carboxamide and 1.0 g. (0.02 mole) of methylisocyanate in 20 ml. of methylene chloride was let stand at ambient temperature for 48 hr. The solution was concentrated to give an oil which crystallized upon standing. The solid was recrystallized from benzene-cyclohexane to yield 0.6 g. (50%) of white solid, m.p. 132°-134° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[N:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=2[N:19]=1.Cl.C1(N2CCNCC2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]3[N:15]=[CH:16][C:17]4[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=4[N:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(c4ccccc4)CC3)ncc2c1=O
Yield: 83 %

Procedure:
A solution of 3.2 g (0.02 mol) of N-phenyl-piperazine in 30 cm3 of toluene is added to 2.8 g (0.01 mol) of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)-pyrimidine dissolved in 30 cm3 of toluene. Reaction takes place practically instantaneously with evolution of heat and the mixture sets solid due to formation of phenylpiperazine hydrochloride. The mixture is diluted with 100 cm3 of ethyl acetate, the solution is filtered, washed with water and dried (MgSO4) and the solvent is evaporated. The residue is recrystallised from 110 cm3 of isopropanol and yields 3.38 g (84%) of 2-(4'-phenyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 186°C.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:22]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=6)[CH:27]=5)=[CH:21][N:20]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][N:26]1[CH:27]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:7][CH2:6][CH2:5][N:4]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:3][CH2:2]5)=[CH:9][CH:10]=4)[CH:15]=3)[N:20]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=3)(=[O:38])=[O:37])[CH:21]=2)[CH:24]=[N:25]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(4-(1,4-diazepan-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.161 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.241 mmol), DIPEA (62 mg, 0.48 mmol) and ethanol (3 mL) to get 100 mg (91.7% yield) of the titled compound. MS: m/z=679.6 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])[NH2:2].O=[C:17]([CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)C>C(O)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]2[CH2:27][CH2:26][CH2:25][C:24]=2[N:1]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[C:12]([F:13])([F:14])[F:15])[N:2]=1)=[O:19])[CH3:22]
Reactant: NNc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)C(=O)C1CCCC1=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc(C(=O)O)cc2C(F)(F)F)c2c1CCC2

Procedure:
4.0 g (18.2 mmol) of 4-hydrazino-3-trifluoromethylbenzoic acid is dissolved in 20 mL of glacial acetic acid, combined with 3.3 g (18.2 mmol) of ethyl oxo-(2-oxocyclopentyl)acetate, and refluxed for 2 hours under a nitrogen atmosphere. After cooling, it is stirred with diethyl ether and the precipitate is suction filtered. Yield: 2.9 g (43%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1([O:22][CH2:21][CH2:20][O:19]1)[CH2:11][CH2:12][CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1SCCCS1)COCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1ccc(COCC2(CCC3SCCCS3)OCCO2)cc1
Reaction time: 1 h

Procedure:
Treatment of 1-benzyloxy-4-(1,3-dithian-2-yl)-butan-2-one (89.8 g) in benzene (3.5 l) with distilled ethylene glycol (220 ml) and p-toluenesulfonic acid (11.7 g) at reflux temperature in a Dean-Stark apparatus for 18 hours gives a mixture which is concentrated to 500 ml in vacuo and allowed to stir for one hour. After the addition of sodium carbonate (10 g), the mixture is then partitioned between ether (300 ml) and brine (300 ml). The aqueous phase is extracted with ether (600 ml) and the combined extracts are washed with 0.05% sodium carbonate (1.2 l), filtered through phase-separating paper and dried (sodium sulfate). The solvent is removed in vacuo to give a residue (102.15 g; 99%). A 200 mg portion of the residue is purified on Quantagram PQ1F plates (chloroform) to give 1-benzyloxy-2,2-ethylenedioxy-4-(1,3-dithian-2yl)-butane (180 mg);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:32](=[O:33])[CH2:31][CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: O=C(O)CC1CCOCC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CC4CCOCC4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and tetrahydropyran-4-yl-acetic acid; MS: m/e=446.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:20])=[O:19].[F:30]C1C=CC(CCN)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:18]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)(=[O:19])=[O:20]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)NCCc3ccccc3)c2)cc1
Reactant: NCCc1ccc(F)cc1
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)NCCc3ccc(F)cc3)c2)cc1

Procedure:
The title compound is prepared as described for 2-chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide, except using 4-fluoro-phenethylamine. 1H NMR (CDCl3): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.60 (m, 1H), 7.08 (m, J=8 Hz, 2H), 7.00 (m, 3H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C22H19ClFNO4S: C, 58.99; H, 4.28; N, 3.13. Found: C, 58.58; H, 4.33; N, 3.12. MS (m/z): 448.0 (M+1)−.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1>CCOCC.CCO>[ClH:3].[ClH:3].[CH3:1][NH:2][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CN
Solvent: CCO
Solvent: CCOCC
Product: CNCc1nc2ccccc2[nH]1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
Methylamine (5.0 g, 0.16 mole) was dissolved in a solution of Et2O (100 mL) and EtOH (5 mL) at 0° C., and 2-chloromethylbenzimidazole (13.4 g, 0.08 mole) was added in small portions. The reaction mixture was stirred at RT for 3 h, then was allowed to stand at RT overnight. More Et2O (200 mL) was added, and the reaction was cooled in an ice bath for 3 h before filtering off the precipitate. The filtrate was saturated with HCl and filtered, and the filtrate was concentrated. Silica gel chromatography (step gradient, 10-25% MeOH/CH2Cl2) yielded the title compound (2.5 g, 13%): 1H NMR (250 MHz, 5:1 DMSO-d6 /CDCl3) δ 7.13-7.54 (m, 4H), 4.11 (s, 2H), 2.50 (s, 3H); MS (ES) m/e 162.0 (M+H)+.
Reaction SMILES: FC(F)(F)CC(=O)[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=1.CCO.Cl>O>[F:18][C:15]([F:16])([F:17])[CH2:14][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([SH:5])=[CH:7][CH:8]=1)=[O:19]
Reactant: O=C(CC(F)(F)F)Nc1ccc(SC(=O)CC(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Temperature: 50 °C
Yield: 44.8 %

Procedure:
S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) were charged to a flask. Concentrated HCl (22.5 mL) was slowly added to keep the temperature below 30° C. The reaction was then heated to 50° C. for 17.5 h. The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) was added. The slurry was filtered and the filter cake was washed with H2O (3×35 mL). The solid was dried under vacuum to produce the desired compound (19.9 g, 58%).
Reaction SMILES: [OH-].[K+].[CH2:3]1[CH:5]2[CH2:6][C:7]3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][NH:10][C:11]=3[CH:4]12.Br[CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CS(C)=O>[O:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:10]2[C:11]3[C@@H:4]4[CH2:3][C@@H:5]4[CH2:6][C:7]=3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)[CH2:20][CH2:21]1
Reactant: BrCC1CCOCC1
Reactant: CCOC(=O)c1n[nH]c2c1CC1CC21
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(CC2CCOCC2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To potassium hydroxide (561 mg, 10.00 mmol) in DMSO (10 mL) was added ethyl 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylate (356 mg, 1.852 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour and added 4-(bromomethyl)tetrahydro-2H-pyran (962 mg, 5.37 mmol). The reaction was stirred at room temperature for 1.5 h, poured into 50 mL of ice cold water and added glacial acetic (0.71 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were concentrated under reduced pressure and purified by HPLC to give the title compound (127 mg, 24% yield) as a yellow solid. LCMS m/z=291.2 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][N:4]=1.S([O-])([O:15][CH3:16])(=O)=O.ClCCCl.[C-:22]#[N:23].[Na+]>O>[C:22]([C:3]1[C:8]([O:15][CH3:16])=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][N:4]=1)#[N:23]
Reactant: COc1cc([N+](=O)[O-])ccn1
Reactant: [C-]#N
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])ccnc1C#N
Temperature: 70 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A mixture of 12.5 g (12.5 moles) of the N-oxide of 3 methoxy-4-nitropyridine, 7.72 ml (1.1 eq.) of methyl sulfate and 70 ml of 1,2-dichloroethane is heated at 70° C. for 2.5 hours. It is allowed to cool and 70 ml of water are added. It is cooled in a salt and ice bath and, in portions, 7.55 g (2.1 moles) of sodium cyanide are added, controlling the temperature so as not to exceed 10° C. After 4 hours stirring, the reaction mixture is extracted with ethyl ether, the organic phase is washed with water, concentrated and the residue chromatographed (ethyl acetate/dichloromethane). There is obtained 7.06 g of a yellow oil (yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 98%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])([O-:8])=[O:7].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][C:3](=[O:4])[CH2:2][Br:1])([O-:8])=[O:7]
Reactant: O=C(Br)CBr
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Under argon atmosphere bromo-acetyl bromide (2.67 mL, 30.66 mmol) dissolved in DCM (15 mL) was added within 15 min to a mixture of 2,4-dinitro-phenol (5.13 g, 27.88 mmol) and pyridine (2.92 mL, 36.24 mmol) in DCM (40 mL) at 0° C. After 1 h at RT, aqueous citric acid solution (10%, 30 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue recrystallized from diethyl ether (75 mL) to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1Cl)=[O:11].[SH2:25].[Na]>CCOCCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1[SH:25])=[O:11]
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)NCCc1ccccn1
Reactant: S
Agent: [Na]
Solvent: CCOCCO
Product: Cc1nn(-c2ccccc2)c(S)c1C(=O)NCCc1ccccn1
Yield: 81.5 %

Procedure:
Using the procedure of Preparation 34, 29.3 g (0.087 mol) of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (2-pyridin-2-yl-ethyl)-amide was reacted with 19.3 g (0.27 mol) sodium hydrogen sulfide in cellosolve to give 24.0 g of the title compound, which was used in Example 22 without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C=O.[C:18](O)(=O)C>C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[C:6]([CH2:18][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: CC(=O)O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1[nH]c(C=O)c(C)c1CN1CCOCC1
Reaction time: 8 h

Procedure:
3,5-Dimethylpyrrole-2-carboxaldehyde (0.5 g, 4 mmole) was added to a solution of morpholine (0.35 g, 4 mmol), formaldehyde 37% (0.32 g, 4 mmol) and acetic acid (2 ml). The mixture was stired overnight at room temperature under nitrogen, then the reaction was diluted with NaHCO3 to pH 8. The aqueous solution was extracted with ethylacetate and the organic layer was dried over Mg SO4. The ethylacetate was evaporated in vacuo to give 0.4 g of pure solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1)[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH2:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[CH3:20]
Reactant: CCC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 62 %

Procedure:
(±)-2-[2-(2-Ethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in example 1c using 0.40 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.25 g of 2-ethylindoline [which can be prepared according to patent WO2009065920] and 0.39 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 250 ml of pyridine and 6.5 ml of N,N-dimethylformamide. After purification by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out successively with 99/1 then 98/2 and 97/3 v/v dichloromethane/methanol mixtures, at a flow rate of 30 ml/min, 0.35 g of (±)-2-[2-(2-ethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is obtained in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([F:17])[C:7]=1[C:8](O)=[O:9]>>[CH3:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([F:17])[C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl

Procedure:
7 ml of thionyl chloride was added to 3.2 g of 2-methyl-3,4,6-trifluorobenzoic acid, followed by heating and refluxing for 1 hour. The reaction mixture was concentrated, giving 3.3 g of 2-methyl-3,4,6-trifluorobenzoyl chloride. Then 5 ml of toluene was added to the resulting 2-methyl-3,4,6-trifluorobenzoyl chloride to give a toluene solution.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.[OH:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>CC#N.O>[CH3:20][C:16]1[N:15]=[C:14]([NH:13][CH:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[C:23]2[C:22]([OH:21])=[C:31]3[C:26]([CH:27]=[CH:28][CH:29]=[N:30]3)=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Oc1cccc2cccnc12
Reactant: Cc1cccc(N)n1
Solvent: O
Solvent: CC#N
Product: Cc1cccc(NC(c2ccc(C(F)(F)F)cc2)c2ccc3cccnc3c2O)n1

Procedure:
The title compound was prepared by both method A and method B presented for the compound of Example 1 with the change that 4-trifluoromethyl benzaldehyde (Sigma), 2-amino-6-picoline and 8-hydroxy-quinoline were used as starting materials. Product obtained (method B): C23H18F3N3O (MW: 409.1); 229 mg, 32.5%); m.p.: 136-138° C.; HPLC (CH3CN/H2O 70:30 Phenomenex C18 254 nm): Tr=10.18 min.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:6][C:5]([CH:11]=[CH2:12])([C:7](OC)=[O:8])[CH2:4]1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[CH3:14][O:13][C:3]1([O:2][CH3:1])[CH2:4][C:5]([CH2:7][OH:8])([CH:11]=[CH2:12])[CH2:6]1
Reactant: C=CC1(C(=O)OC)CC(OC)(OC)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1(CO)CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of methyl 3,3-dimethoxy-1-vinylcyclobutanecarboxylate (2.02 g, 10.09 mmol) in THF (20 mL) was added DIBAL-H (1.04M in toluene, 29 mL, 30.16 mmol) at 0° C. under argon, and the mixture was stirred for 30 minutes at 0° C. To the mixture was carefully added MeOH (29 mL) and Na2SO4.10H2O (29 g), and the mixture was stirred overnight. The mixture was filtered and evaporated under reduced pressure. And the residue was diluted with hexane/EtOAc=1:1 and filtrated through the pad of silica gel and concentrated in vacuo to give (3,3-dimethoxy-1-vinylcyclobutyl)methanol (1.42 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:15]([CH3:16])[C:3]=12.[C:24](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:16][C:15]1[C:3]2[C:2](=[O:1])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([CH3:24])[C:4]=2[S:13][C:14]=1[CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)c1cnc2sc(CN3CCOCC3)c(C)c2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.7 %

Procedure:
Ethyl 4-hydroxy-3-methyl-2-(morpholin-4-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (Preparation 27, 1.47 g) and potassium carbonate (1.21 g) are suspended be in DMF (25 mL). The mixture is warmed until the ester dissolves and iodomethane (0.30 mL) is added. The reaction mixture is allowed to stir at room temperature for 20 h. The mixture is then poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (2×25 mL), dried (Na2SO4), and partially concentrated. Hexanes are added and the resulting solid is filtered to afford 0.70 g of the title compound as a light yellow solids Physical characteristics. M.p. 172-173° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.41, 4.19, 3.81, 3.65, 3.59, 2.48, 2.46, 1.27; MS (ESI+) m/z 351 (M+H)+. Anal. Found: C, 58.04; H, 6.54; N, 7.77; S, 8.97.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CC(CNC(=O)c1cccc(Cl)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=432.1, tR (minutes, Method G)=2.58. [α]D20=+17.42 (c=6.6 mg/mL,CHCl3)
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: Clc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-chloroaniline by Procedure A. The product was isolated by filtration and recrystallisation to give the title compound as a hydrochloride salt (white solid, mp 238-240° C.). MS(ES+) m/z 244 ([M+1]+, 100).