Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[S:25])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=S
Temperature: 70 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A round-bottomed flask with (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (compound 10a, 3.0 g, 14.0 mmol) and Lawesson's reagent (6.8 g, 16.8 mmol) was flushed with nitrogen. Dry THF (40 ml) was added as the solvent. The reaction mixture was stirred at 70° C. under nitrogen for 8 hours. After cooled to room temperature, the resulting mixture was evaporated under reduced pressure and purified by column chromatography (ethyl acetate:n-hexane=1:2) to yield pure product 11a (2.7 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1.[CH3:24]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH2:19][O:20][CH3:24])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: CI
Reactant: OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a cooled solution of NaH (60% in mineral oil, 12 mg, 0.3 mmol) in DMF (0.5 mL) under an atmosphere of nitrogen, was added a solution of (7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example 35, 30 mg, 0.10 mmol) in DMF (0.5 mL). The reaction was stirred for 10 minutes. Methyl iodide (0.019 mL, 0.3 mmol) was added and the reaction was stirred for an additional 25 minutes at 0° C. before being quenched with a sat. NH4Cl (aq.) solution. The aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (19 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=2.0 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.39-7.27 (m, 4H), 5.19 (s, 2H), 4.62 (s, 2H), 3.45 (s, 3H). [M+H]=314.2.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:15][C:16]=1[O:21][C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1ccc(Cl)c(Oc2ccncc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(Oc2ccncc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-(4-pyridyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 9-[4-chloro-3-(4-pyridyloxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide water gave a yellow crystalline solid of melting point 242-244° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].[CH:41](=[O:43])[CH3:42]>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH:41]([OH:43])[CH3:42])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]
Reactant: CC=O
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C(C)O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (6 ml) stirred under argon at 0° C., was added butyl lithium (2.5M in hexane) (0.80 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (preparation described in, for example, EP 1,731,512) (404 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added acetaldehyde (0.14 ml) and the reaction mixture was stirred at −85° C. for 1.5 hours. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/diethyl ether 60:40) to give 4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.98-7.96 (d, 1H), 7.60-7.45 (m, 5H), 4.09-4.08 (m, 1H), 3.96-3.91 (m, 1H), 3.91 (s, 3H), 2.63 (s, 3H), 1.07 and 0.94 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C[O-].[Na+].CS(C)=O.[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32]Cl>O>[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32][O:7][C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])=[O:8]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1c(Cl)ccc2cc(Cl)cnc12)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
33 parts by weight of 2-nitrobenzoic acid, 40 parts by weight of 30% strength sodium methylate solution and 440 parts by weight of dimethylsulfoxide are stirred for 2 hours at 100° C. Thereafter, 49 parts by weight of 3,7-dichloro-8-chloromethylquinoline are introduced and the reaction mixture is stirred for a further 2 hours at 100° C. The solution is then cooled, water is added and the precipitated solid is filtered off under suction and recrystallized from toluene. 69 parts by weight (92% of theory) of 3,7-dichloro-8-[(2-nitrophenyl)-carbonyloxymethyl]-quinoline of melting point 152° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([BH3-])#N.[Na+].[OH-].[K+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:20][CH2:19][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=CCCc1cccnc1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCCNCCCc2cccnc2)cc1
Reaction time: 2 h
Yield: 29.5 %

Procedure:
A stirred mixture of 3-(3-pyridyl)propionaldehyde (4.40 g, 32.5 mmoles) and 3-phenylpropylamine (5.30 g, 1.2 equiv.) in methanol at rt was treated with sodium cyanoborohydride (1 g, 0.5 equiv.). After 1 h at rt the mixture was further treated with solid potassium hydroxide (3.6 g, 2 equiv.) and stirring was continued for 2 h. The resulting mixture was partitioned between brine and ether. The aqueous layer was extracted with ether and the combined ether extracts were extracted with 6N HCl (3×). These aqueous extracts were basified with solid potassium hydroxide and extracted with ether (3×), dried over sodium sulfate and concentrated in vacuo. The residue was distilled under high vacuum to give the product as a colorless oil (2.44 g, 30%), b.p. ca. 162° C./0.5 mm Hg.
Reaction SMILES: COC1C=CC2C=C(C3C=CC=CC=3N)CCCC=2C=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[C:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH:64]=3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[C:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH:64]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CCCC(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Agent: COc1ccc2c(c1)CCCC(c1ccccc1N)=C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1=Cc2ccc(OC)cc2CCC1

Procedure:
Synthesized from 2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (454 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (345 mg). This compound (343 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (309 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Ethyl-4-{[4-({4-[(3-fluoro-5-morpholin-4-ylbenzoyl)amino]-1-naphthyl}oxy)pyrimidin-2-yl]amino}piperidine-1-carboxylate (Compound B341) Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 4-amino-piperidine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. Mp: 122-124° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.14 (t, J=6.9 Hz, 3 H), 1.17-1.26 (m, 2 H), 1.73 (bs, 2 H), 2.82 (bs, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.34 (bs, 1 H), 3.77 (t, J=4.8 Hz, 4 H), 3.89 (bs, 1 H), 3.96-4.01 (m, 2 H), 6.36 (bd, 1 H), 7.04 (d, J=12.4 Hz, 1H), 7.12 (s, 1 H), 7.27 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.56-7.62 (m, 3 H), 7.82 (d, J=7.6 Hz, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: C([Li])CCC.[I-].[CH3:7][C:8]1([CH2:13][CH2:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:12][CH2:11][CH2:10][O:9]1.[Cl:35][CH:36]=[C:37]1[CH:43]=[CH:42][C:41]2[CH:44]=[C:45]([CH:48]=O)[CH:46]=[CH:47][C:40]=2[O:39][CH2:38]1.O>O1CCCC1.ClCCl>[Cl:35][CH:36]=[C:37]1[CH:43]=[CH:42][C:41]2[CH:44]=[C:45]([CH:48]=[CH:15][CH2:14][CH2:13][C:8]3([CH3:7])[O:9][CH2:10][CH2:11][O:12]3)[CH:46]=[CH:47][C:40]=2[O:39][CH2:38]1
Reactant: CC1(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Reactant: O=Cc1ccc2c(c1)C=CC(=CCl)CO2
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(CCC=Cc2ccc3c(c2)C=CC(=CCl)CO3)OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
0.206 ml (0.41 mmol) of a 1.9M n-butyllithium solution is added dropwise to 207 mg (0.435 mmol) of [3-(2-methyl-1,3-dioxolan-2-yl)propyl](triphenyl)phosphonium iodide in suspension in 3.2 ml of tetrahydrofuran cooled to 0° C. The medium is stirred for one hour and then the ylide is added at 0° C., via a hollow tube, to 48 mg (0.22 mmol) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carbaldehyde, prepared according to example 72, in solution in 3.6 ml of tetrahydrofuran. The medium is stirred at ambient temperature for 25 minutes and then water and dichloromethane are added. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are then washed with brine, are then dried and are then finally concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to give 47 mg (71%) of 3-(chloromethylene)-7-[4-(2-methyl-1,3-dioxolan-2-yl)-1-butenyl]-2,3-dihydro-1-benzoxepin in the form of a mixture of four diastereoisomers in a Z/E (60/40) ratio for the unsaturated chain and a Z/E ratio (85/15) for the chloromethylene functional group; 1H NMR (300 MHz, CDCl3) ZZ isomer: 1.32 (s, 3H), 1.81 (m, 2H), 2.44 (m, 2H), 3.9 (m, 4H), 4.86 (s, 2H), 5.63 (m, 1H), 6.31 (m, 4H), 6.96 (m, 3H).
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][CH2:8][N:9]([C:11](=[O:43])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)[CH3:10])(C)(C)C.[Li+].[OH-].Cl>C1COCC1.O>[CH:21]1([CH2:20][CH:19]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[O:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:9]([CH3:10])[CH2:8][CH2:7][C:6]([OH:44])=[O:5])=[O:43])=[CH:13][CH:14]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCC(=O)O)C(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a mixture of (±)-3-({4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoyl}-methyl-amino)-propionic acid tert-butyl ester (7.4 mg, 0.012 mmol) in THF (0.5 mL) is added LiOH (1 N aqueous, 0.5 mL) and stirred at 70° C. overnight. The reaction mixture is acidified with 1N HCl (1.0 mL), diluted with water, and extracted with EtOAc (3×5 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. to provide (±)-3-({4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoyl}-methyl-amino)-propionic acid (4.6 mg, 68%) as a clear syrup. MS (ES): 554.2 [M+H]+.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH2:23]>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH:23][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cc(Cl)cc(Cl)c2)c(=O)c1=O
Yield: 76.7 %

Procedure:
A solution of 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol, Example 3), 3,5-dichlorobenzylamine (0.88 g, 5 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 3 days. The reaction mixture was processed as in Example 2, Step 4. The crude product was recrystallized (twice) from methanol to provide 1.309 g of the title compound as a white solid: mp 257°-258° C. (dec). MS (m/z) 340/342/344 (M+). HPLC indicates a major component (97%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:29]=[C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=4)[N:28]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Reactant: N=C(N)Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(C(F)(F)F)cc3)ncc1CC2
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (200 mg, 1.02 mmol), N-(4-trifluoromethyl-phenyl)-guanidine nitrate (273 mg, 1.02 mmol), NaOH (41 mg, 1.02 mmol) and 2-methoxyethanol (1.25 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) followed by crystallisation from EtOAc gave the pure title compound as a white crystalline solid (30 mg, 8%): mp 212-213° C. Anal. RP-HPLC: tR 21.8 min (10-70% MeCN, purity 95%). 1H-NMR (CDCl3): δ 8.17 (s, 1H, Py-H), 7.71 (d, 2H, J 8.4, Ph-H), 7.52 (d, 2H, J 8.4, Ph-H), 7.16 (s, 1H, NH), 3.04 (t, 2H, J 6.6, CH2), 2.94 (t, 2H, J 6.6, CH2), 2.72 (s, 3H, CH3). MS (ESI−): m/z 360.95 (M−H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](O)[CH3:17].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:16][CH2:17][O:11][C:10]([C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
N-tert-Butoxycarbonylprolin (24.38 g, 113 mmol) was dissolved in dichloromethane (60 ml). Ethanol (7.9 ml, 135 mmol) and 4-dimethylaminopyridine (1.52 g, 12.5 mmol) were added. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (23.88 g, 125 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. Ethyl acetate (400 ml) was added. It was washed with a 10% aqueous solution of sodium hydrogen sulfate (300 ml). The aqueous phase was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate (1:4) as eluent, to give 17.11 g of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[NH2:13][C:14](N)=[O:15].N>O>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:14]([NH2:13])=[O:15])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: NC(N)=O
Agent: N
Solvent: O
Product: COc1cccc2sc(NC(N)=O)nc12
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-methoxy-benzothiazole (330 mg, 1.83 mmol) and urea (1.1 g, 1.83 mmol) were heated together for 1 h at 170° C., with evolution of ammonia. After allowing to cool to r.t., water (10 ml) was added and the mixture was vigorously stirred. The solid was then filtered, washed with water (10 ml) followed by ethanol (10 ml) and dried at 60° C. under vaccum (0.05 mmHg). The title product was afforded as an off-white solid (300 mg, 73% yield), MS: m/e=223 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)[N:20]=[C:19]([CH3:37])[N:18]=2>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:38][C:39]([CH3:41])([OH:42])[CH3:40])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1)[N:20]=[C:19]([CH3:37])[N:18]=2
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Add trifluoroacetic acid (10 mL) to a solution of tert-butyl 4-[8-(2-chlorophenyl)-9-(2-hydroxy-2-methyl-propyl)-2-methyl-purin-6-yl]piperazine-1-carboxylate (1.9 g, 0.0038 mol) in dichloromethane (10 mL) at 0° C. and stir for 2 h at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the title compound (1.5 g). ES/MS m/z 401 (M+1).
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)c(F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To the solution of methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenoxy)-2,2-dimethylbutanoate (176 mg, 0.30 mmol) in MeOH/THF (1 mL/1 mL) was added excessive LiOH (1N aqueous solution). The reaction mixture was stirred at r.t. overnight. The reaction was quenched by adding 6N HCl to PH 2. The mixture was concentrated under reduced pressure to remove MeOH and THF. DCM (30 mL) was added. The reaction mixture was washed with brine (30 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford slightly yellow solid product (120 mg, 70%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)=[N:19][CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccc(Cl)cn3)CC2)cc1
Yield: 113.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.5 g), 1-(5-chloropyridin-2-yl)piperazine (1.5 g) and potassium carbonate (1.6 g) in dimethylformamide (20 ml) was stirred at 70-80° C. for 8.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (3.1 g). The obtained brown solid was crystallized ethyl acetate to give the title compound (1.3 g) as pale-yellow crystals,