Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:22]=[O:24])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(N=C=O)cc1
Temperature: 75 °C
Yield: 159.1 %

Procedure:
To a mixture of (4-aminophenoxy)-acetic acid methyl ester 3 (15 g, 82.87 mmol) and triethylamine (16.77 g, 165.73 mmol) in toluene (225 ml) under nitrogen atmosphere at 0° C. was added triphosgene (9 g, 30.33 mmol) in one lot. The reaction was exo-thermic and the temperature rose to 25° C. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered off, and toluene was distilled off under vacuum to get crude 4, which was vacuum distilled to get pure 4 (10 grams, 58.3%) as a white powder with an m.p between 50-53° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][OH:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][O:5][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1cc(C)c(CO)c(C)c1
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(COC(=O)CCC(=O)O)c(C)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A mixture of 1.50 g (0.01 mol) of 2,4,6-trimethylbenzyl alcohol, 1.00 g (0.01 mol) of succinic acid anhydride, 3.25 g (0.01 mol) of cesium carbonate, and 100 ml of dioxane was stirred at reflux temperature for 4 hours. The reaction mixture was cooled to room temperature and then filtered to remove the solid cesium carbonate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (acetone-hexane) to provide 1.167 g of succinic acid mono-(2,4,6-trimethylbenzyl) ester (46.62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[SH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C=CC=CC1=O>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([S:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C)c(S)c(C)c1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of 2,4,6-trimethylbenzene-1-thiol (231 mg, 1.52 mmol) in 1-methyl-2-pyridone (2 mL) was added NaH (58 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (131 mg, 0.51 mmol) in 1-methyl-2-pyridone (2 mL) was added to the mixture. The mixture was heated at 60° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 180 mg (94%) of 7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C@H:22]([NH2:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][C@H:22]([NH:29][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e=383.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:45][CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51]>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:53])[CH3:52])=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C[Si](C)(C)CCOCOc1ccccc1CCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3OCOCC[Si](C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57(c)] with 1-chloromethyl-(2-trimethylsilyl-ethoxymethoxy)-benzene [Example 17(c)] there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-(4-{3-[2-(2-trimethylsilanyl-ethoxymethoxy)-benzyloxy]-propoxy}-phenyl)-piperidine-1-carboxylate as a colourless oil; MS: 746 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[CH:14]=[N:15][N:16]2[C:21](=O)[CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[NH:18][C:17]=12.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:42])=O>>[Cl:42][C:21]1[N:16]2[N:15]=[CH:14][C:13]([CH2:12][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=3[CH3:1])=[C:17]2[N:18]=[C:19]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(Cc2cnn3c(=O)cc(N4CCOCC4)[nH]c23)cccc1C(F)(F)F
Solvent: CCN(CC)c1ccccc1
Product: Cc1c(Cc2cnn3c(Cl)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.52 g, 1.32 mmol) and N,N-diethylaniline (0.43 g, 2.92 mmol) under nitrogen was added neat phosphoric trichloride (1.12, 6.63 mmol) dropwise during 15 minutes. The reaction mixture was stirred at 80° C. for 3 hours. Reaction mixture was concentrated under reduce pressure. The residue was dissolved with DCM (50 mL) and water (15 mL). The pH of aqueous layer was adjusted to 8˜9. Two layers were separated. Aqueous layer was then extracted with DCM (30 mL×3). The crude material was then purified with silica gel column chromatography (CH3OH/DCM 0-10%) to provide the titled product. (450 mg, 83%); LC/MS: MS (ES+) m/e 378 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (br. s., 1H) 3.45 (d, J=5.05 Hz, 3H) 3.63-3.71 (m, 4H) 4.00 (s, 2H) 5.55 (s, 1H) 7.16 (s, 2H) 7.22-7.30 (m, 1H) 7.30-7.40 (m, 1H) 7.46 (dd, J=7.83, 1.77 Hz, 1H) 7.72 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:60][C:61]1[CH:62]=[C:63]2[C:67](=[CH:68][CH:69]=1)[N:66]([NH2:70])[CH:65]=[CH:64]2>C(Cl)Cl.O.CCOC(C)=O>[Br:60][C:61]1[CH:62]=[C:63]2[C:67](=[CH:68][CH:69]=1)[N:66]([NH:70][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:65]=[CH:64]2
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Nn1ccc2cc(Br)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (596 mg, 2.57 mmol), PyAOP (2.63 mmol), and DIPEA (830 μL, 4.75 mmol) in DCM (20 mL) is stirred at rt under N2 for 10 min. 5-Bromoindol-1-ylamine (500 mg, 2.37 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 2% MeOH in DCM to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-bromo-indol-1-yl)-amide (246 mg, 24%) as a solid. MS: 425 (M) & 427 (M+2). 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 9.24 (s, 1H), 8.34 (d, 1H), 8.20-8.15 (m, 1H), 7.84 (d, 1H), 7.68-7.61 (m, 1H), 7.59 (d, 1H), 7.50-7.43 (m, 2H), 7.35 (dd, 1H), 6.57 (dd, 1H), 2.78 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:6]2=[N:7][CH:8]=1.[Cl-].[NH+]1C=CC=CC=1>N1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2c(c1)C(=O)c1ccccc1-2
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ncc(O)cc21
Temperature: 180 °C
Yield: 10.6 %

Procedure:
Under an argon atmosphere, 3-methoxy-indeno[1,2-b]pyridin-5-one (0.545 g) and pyridinium chloride (5.89 g) were mixed with pyridine (1.0 ml). The reaction mixture was stirred with heating at 180° C. for 30 min while evaporating pyridine, and further stirred with heating at 200° C. for 4 hr. The mixture was cooled to room temperature, water was added and the mixture was stirred for 30 min. This slurry was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.054 g). The obtained solid was used for the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[C:27]1([CH:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCCCCNC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 2.0 g (13.4 mmol) 3-(3-pyridyl)-acrylic acid, 3.0 g (29.6 mmol) TEA, 2.4 g (15.6 mmol) 88% HOBT, 3.0 g (15.6 mmol) EDC and 4.0 g (13.4 mmol) 4-diphenylacetylamino-butylamine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:12]1[CH:13]=[CH:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:11]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Agent: Cl
Product: CN(C)CCn1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 3 using 3-(4-nitrophenyl)-1H-pyrazol (2.4 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride provided the title compound. ESMS [M+H]+: 261.2.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH3:10][NH:11][C:12](=[N:15][C:16]#[N:17])SC>C(#N)C>[C:16]([NH:15][C:12]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[N:11][CH3:10])#[N:17]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CNC(=NC#N)SC
Solvent: CC#N
Product: CN=C(NC#N)N1CCc2[nH]cnc2C1
Yield: 30.9 %

Procedure:
A solution of 1.23 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.29 g of N,S-dimethyl-N'-cyano-isothiourea ##STR3## in 15 ml of acetonitrile is refluxed for 21 h. After evaporation to dryness, chromatography on silica gel (ethyl acetate-ethanol as eluant) of the residue gives 630 mg of the pure title compound, m.p. 240°.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:6][CH2:7][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@H:18]5[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]5[NH:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:3][CH2:4]2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To the solution (3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (99 mg, 0.25 mmol) in dry DMF (3 mL) was added cyclopropanecarboxylic acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and stirred at room temperature for 1 h. The solvent was removed in vacuo, dichloromethane added (15 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to yield the title compound (59 mg, 61%) as white powder. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.71-0.89 (m, 4H), 1.00 (s, 3H), 1.28-1.46 (m, 5H), 1.50-1.68 (m, 2H), 1.68-1.89 (m, 8H), 1.89-2.00 (m, 2H), 2.11-2.31 (m, 2H), 2.86-3.02 (m, 2H), 3.02-3.14 (m, 2H), 3.47-3.70 (m, 4H), 3.75-3.91 (m, 1H). MS (M+1): 389.2.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CS([C:15]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][N:16]=1)(=O)=O>CS(C)=O>[F:24][C:21]([F:22])([F:23])[C:19]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][N:16]=[C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[N:20]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccccc2)c(C(F)(F)F)n1
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncc(-c3ccccc3)c(C(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With cooling, 2.2 g of powdered potassium hydroxide are added to a solution of 2.1 g of 4-aminophenol in 50 ml of dimethylsulfoxide and the mixture is stirred for 1 hour to form a clear solution. To the batch are then added, in portions, 6 g of 2-methylsulfonyl-4-trifluoromethyl-5-phenylpyrimidine and the mixture is stirred for 4 hours at room temperature. The mixture is then poured into ice-water and extracted with ether. The washed and dried ethereal extracts yield a product of m.p. 123°-126° C., which is the title compound of formula ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37]
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CNCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4.84 g (28.3 mmol) of 2-chloro-6-nitrotoluene was dissolved in 50 ml of benzene. 50 mg of perbenzoic acid and 6.0 g (34 mmol) of N-bromosuccinimide were added to the obtained solution, and the obtained solution was stirred at 80° C. overnight. The reaction solution was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. The crude product was dissolved in 100 ml of ethanol. 11.9 g (84.9 mmol) of glycine ethyl ester hydrochloride and 8.9 g (106 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 80° C. for 4 hours. The insoluble matter was removed by the filtration, and the solvent was evaporated. After the extraction with ethyl acetate followed by washing with 1 N hydrochloric acid, the obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH2:20]>>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:20][CH3:19])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CCCCC1
Product: CNc1ccc(C(=O)C2CCCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 7b from 4-(cyclohexylcarbonyl)-2-nitro-chlorobenzene and methylamine solution.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-fluoro-4-methylnitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[N:13]1([CH2:18][CH2:19][C:20](=[S:22])[NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>>[N:13]1([CH2:18][CH2:19][C:20]2[S:22][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:21]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: NC(=S)CCn1ccnc1
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Product: c1ccc2c(c1)Cc1sc(CCn3ccnc3)nc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, 3-(1-imidazolyl)propanethioamide hydrochloride
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([CH2:9]O)[CH2:8][CH2:7]1.[Br-].[Li+].[O:13]1[C@@H:25]2[C@@:26]34[CH2:28][CH2:29][NH:30][C@@H:20]([C@:21]3([OH:32])[CH2:22][CH2:23][C:24]2=[O:31])[CH2:19][C:18]2=[C:27]4[C:14]1=[C:15]([OH:33])[CH:16]=[CH:17]2>CN(C=O)C.C(N(CC)CC)C>[CH2:7]1[CH:6]([CH2:9][N:30]2[C@@H:20]3[CH2:19][C:18]4[CH:17]=[CH:16][C:15]([OH:33])=[C:14]5[O:13][CH:25]6[C:24]([CH2:23][CH2:22][C@:21]3([OH:32])[C@:26]6([C:27]=45)[CH2:28][CH2:29]2)=[O:31])[CH2:8]1
Reactant: OCC1CC1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3)[C@H]1O5
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Temperature: 2.5 °C

Procedure:
Methanesulphonyl chloride (76 kg) was added to the mixture of cyclopropyl methanol (50 kg) and triethylamine (192 L) in DMF (400 L) maintained at 0-5° C., the reaction mixture was maintained at 0-5° C. for 3.0 hrs. Lithium bromide (60 Kg) was added to reaction mixture at 0-15° C. and maintained for 10-15 minutes. Noroxymorphone (40 Kg) was added to above reaction mixture at 0-5° C. and temperature raised to 65-70° C. over 1.0 hr period and maintained for 14-15 hrs. After completion of reaction it was quenched in ice-water below 20° C. and the product was extracted with ethylacetate. The ethylacetate layer was concentrated and the product was isolated with MDC and cyclohexane mixture at 10-15° C. Yield=35.3 Kg.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:17](=[O:19])=[O:18].CCOCC>O1CCCC1.CCCCCC>[C:1]1([C:7]2[S:8][C:9]([C:17]([OH:19])=[O:18])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: c1ccc(-c2cccs2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)s1
Reaction time: 1 h

Procedure:
A solution of 2-phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydrous tetrahydrofuran (THF) is treated dropwise with a solution of n-butyl lithium (0.11 mole) in hexane (2 M solution). Thereafter the mixture is stirred for 1 hr. The resulting black solution is poured onto 50 g of solid CO2 covered with ether. When all the CO2 is evaporated, the mixture is treated with 200 ml of water, acidified with 10% HCl and extracted with ether. The extract is washed with 5% NaOH. The latter washings are cooled and rendered acidic with 20% HCl. The resulting precipitate is collected and recrystallized from 100 ml CCl4 to give 5-phenyl 2-thiophenecarboxylic acid, mp 180° C, γmaxCHCl 3 1665 cm-1, as yellow green crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[Cl:45]CCl.Cl>CO>[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Yield: 84 %

Procedure:
(R)-[3-[1-((S)-2-Hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.16 g, 0.25 mmol) and 2 mL of dichloromethane were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of methanol was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 30 (120 mg, yield 84%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: OCc1csc(Nc2ccc(F)cc2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1csc(Nc2ccc(F)cc2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 3.03 g of 2-p-fluoroanilinothiazol-4-ylmethanol, 8.5 g of pyridine sulfur trioxide complex, 7.5 ml of triethylamine and 140 ml of dimethyl sulfoxide. giving the title compound as pale brown prisms.