Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.O[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.Cl.C(OCC)(=O)C>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([O:13][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH2:15][CH2:16]1
Reactant: CN1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
N-(1-Methyl-4-piperidyloxy)phthalimide may be obtained in the following manner: diethyl azodicarboxylate (53.8 g) is added in the course of 90 minutes at a temperature in the region of 0° C. to a suspension of 4-hydroxy-1-methylpiperidine (30.6 g), N-hydroxyphthalimide (43.7 g) and triphenylphosphine (68.3 g) in tetrahydrofuran (450 cc). The suspension obtained is stirred at a temperature in the region of 20° C. for 18 hours and the reaction mixture is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The product obtained is taken up with ethyl acetate (500 cc) and the suspension obtained is filtered. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The product obtained is redissolved in N aqueous hydrochloric acid solution (500 cc). The suspension obtained is filtered and the filtrate is extracted 3 times with ethyl ether (300 cc in total) and brought to a pH in the range of 10 by adding N aqueous sodium hydroxide solution (500 cc) The crystals which appear are separated by filtration, washed 3 times with distilled water (300 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 20° C. N-(1-Methyl-4-piperidyloxy)phthalimide (19 g) is thereby obtained in the form of beige crystals, m.p. 90° C.
Reaction SMILES: [CH:1]1(C(C2C=C(OC)C=C(OC)C=2)=O)CCCCC1.[CH:19]1([C:24]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=2)([CH3:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>CCCCCC.C(OCC)(=O)C>[CH:19]1([C:24]([C:27]2[CH:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=2)([CH3:26])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:1]1
Reactant: COc1cc(OC)cc(C(C)(C)C2CCCC2)c1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCC2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C(C)(C)C2CCCCC2)c1

Procedure:
Compound 14 was prepared from Compound 7 using the same procedure as described above for Compound 13. Yield 3.69 g (70.3%) as an oil. Rf=0.55 (hexane:ethyl acetate 95:5); IR (neat) 2932, 1457, 1422, 1208, 1066 702 cm−1; 1H NMR δ 6.48 (d, J=2.4 Hz, 2H), 6.35 (t, J=2.1 Hz, 1H), 3.80 (s, 6H), 1.72–1.55 (m, 6H), 1.45–1.39 (m, 1H), 1.21 (s, 6H), 1.18–1.05 (m, 2H), 0.97–0.85 (m, 2H); 13C NMR δ 160.52, 153.48, 105.35, 96.64, 55.44, 49.28, 41.06, 28.18, 27.44, 26.96, 25.50; MS: (ESI, Pos.) m/z 263 ([M+H]+).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][O:40][CH2:41][CH2:42]Br>CN(C)C=O>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH2:42][CH2:41][O:40][CH3:39])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CCOC)C2)ncc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in dimethylformamide (3 mL) and cesium carbonate (65 mg, 0.200 mmol, 3.0 eq) was added followed by 2-bromoethyl methyl ether (11.2 mg, 0.0804 mmol, 7.6 μL, 1.2 eq). The reaction was stirred at room temperature for 72 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 2-{5-chloro-2-[10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a yellow foam (8.25 mg, 24%). LCMS (m/e) 507 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.66 (d, 1H, J=8.0 Hz), 8.08 (s, 1H), 7.50-7.40 (m, 2H), 7.34 (d, 1H, J=2.1 Hz), 7.30-7.20 (m, 1H), 7.10-6.98 (m, 2H), 6.93 (s, 1H), 6.19 (bs, 1H), 3.48 (t, 2H, J=6.0 Hz), 3.33 (s, 3H), 3.03 (d, 3H, J=4.9 Hz), 3.0-2.93 (m, 3H), 2.92-2.86 (m, 1H), 2.61 (t, 2H, J=6.0 Hz), 2.35-2.26 (m, 2H), 2.24-2.17 (m, 2H), 1.63-1.57 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12](OC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[OH:20][CH2:21][CH2:22][NH:23][NH2:24].C(N(CC)CC)C.O>C(O)C>[NH2:17][C:16]1[N:23]([CH2:22][CH2:21][OH:20])[N:24]=[C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[C:13]=1[C:14]#[N:15]
Reactant: CCOc1cc(C(OC)=C(C#N)C#N)ccc1OC
Reactant: NNCCO
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(-c2nn(CCO)c(N)c2C#N)ccc1OC
Temperature: 25 °C

Procedure:
2-((3-ethoxy-4-methoxyphenyl)(methoxy)methylene)malononitrile (200 mg, 0.78 mmol), 2-hydroxyethylhydrazine (0.056 mL, 0.78 mmol), and triethylamine (0.10 mL, 0.78 mmol) were combined in ethanol (5 mL) and heated to reflux for 90 minutes. The reaction was then cooled to RT, water was added and the aqueous phase was extracted three times with EtOAc, CH2Cl2, and CHCl3. The organic phase was concentrated and carried onto the next step without further characterization. ESI-MS (M+H)+ m/z calcd 303.1, found 303.0.
Reaction SMILES: [NH2:1][O:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([OH:14])[C:10](=[CH:12][CH:13]=1)[OH:11])(=[O:6])=[O:5].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21](=O)[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[N:44]4[N:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=[C:43]4[N:42]=[C:41]([CH3:52])[CH:40]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[N:20]=1.[OH-].[Na+:55].O.CO>O.CO>[Na+:55].[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:1]/[O:2][CH2:3][S:4]([C:7]2[CH:13]=[CH:12][C:10]([OH:11])=[C:9]([OH:14])[CH:8]=2)(=[O:5])=[O:6])/[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[N:44]4[N:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=[C:43]4[N:42]=[C:41]([CH3:52])[CH:40]=2)=[C:30]3[C:34]([O-:36])=[O:35])=[O:23])[N:20]=1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Reactant: COC(=O)c1nc2nc(C)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc2nc(C)cc(SCC3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1

Procedure:
122 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with 236 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[[2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid according to the procedure described in Example 7. The crude product obtained was suspended in 10 ml of water and brought into solution by the slow addition of 0.1N sodium hydroxide solution, with care being taken that the pH of the solution did not exceed 7. By chromatography on MCI gel CHP 2OP using water as the elution agent as well as water/methanol mixtures with increasing amounts of methanol and lyophilization of the concentrated product fractions, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl] thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH2:10]([O:22][C:23](=[O:28])[CH2:24][C:25]([CH3:27])=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:29](S)[CH3:30].Cl>C1(C)C=CC=CC=1>[CH2:10]([O:22][C:23](=[O:28])[CH2:24][C:25]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:9])=[C:29]([CH3:30])[CH:5]=1)([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=1)[CH3:27])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCOC(=O)CC(C)=O
Reactant: Cc1cccc(C)c1O
Reactant: CCS
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)CC(C)(c1cc(C)c(O)c(C)c1)c1cc(C)c(O)c(C)c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
In a four-necked flask, 122 g of 2,6-dimethyl-phenol (1 mol), 135 g of acetoacetic acid dodecyl ester (0.5 mol) and 0.7 g of ethyl mercaptan were mixed and at 10° C gaseous hydrogen chloride was passed through this mixture for 8 hours. The mixture was stirred for 24 hours at 10° C, then toluene was added and the resulting water was distilled off in an azeotropic mixture. Upon cooling, the 3,3-bis(4'-hydroxy-3' ,5'-dimethylphenyl)butanoic acid dodecyl ester precipitated from the toluene solution in crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[O:5][N:4]=1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][C:6]2[O:5][N:4]=[C:3]([CH3:2])[CH:7]=2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: Cc1cc(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)on1
Yield: 29.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-methylisoxazol-5-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 32, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxamide (9 mg, 29.2%). 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.54 (d, 2H), 7.27 (t, 2H), 7.19 (m, 4H), 6.67 (m, 4H), 6.20 (d, 1H), 4.48 (1H), 3.88 (m, 3H), 2.66 (m, 4H), 2.15 (s, 3H), 1.91 (m, 2H). MS (EI) for C30H28FN3O4: 514.6 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 135.6 %

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-L-tyrosine (5.00 g), methyl chloroacetate (1.45 g) and potassium carbonate (1.85 g) in N,N-dimethylformamide (75 ml) was stirred for 20 hours at room temperature. The mixture was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and then brine. After dried over magnesium sulfate, the extract was evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosine (6.40 g), mp. 69°-73° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH:21]=1>CN(C)C=O.C(N(CC)CC)C.ClCCl>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=C(O)CCCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1cccnc1)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Yield: 88.3 %

Procedure:
A mixture of 2.0 g of 4-diphenylmethylpiperidine in 5 mL of dimethylformamide and 4.2 mL of triethylamine was treated at 0° C. with a solution composed of 5 mL of dimethylformamide and the acid chloride prepared from 2.0 g of 3-pyridine butanoic acid. After 15 minutes the mixture was diluted with dichloromethane, filtered and evaporated to dryness. The residue was partitioned between toluene and 1N sodium hydroxide and the organic layer was washed with brine, dried over sodium sulfate and evaporated to give 3.3 g of crude oil. Purification was accomplished by chromatography on a Waters Prep 500 HPLC using silica gel columns and eluting with 98:2 ethyl acetate-triethylamine. The product consisted of a colorless oil which was dried under vacuum at 70° C. to give 2.8 g (86%) of 4-diphenylmethyl-1-[1-oxo-4-(3-pyridinyl)butyl]piperidine, 0.1 molar ethylacetate solvate. Analysis Calculated for C27H30N2O.O.1C4H8O 2 : C, 80.79; H, 7.62; N, 6.88. Found: C, 80.91; H, 7.57; N, 6.81.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid methyl ester (656 mg, 1.99 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (920 mg, 21.9 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid (570 mg, 91%) as a tan solid: mp 91-94° C.; EI-HRMS m/e calcd for C20H26O3 (M+) 314.1881, found 314.1872.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Sc1ccc(Cl)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Sc3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chlorobenzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 251.7-253.3° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.62 (m, 5H), 6.39 (s, 1H), 5.78 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d,/282 MHz) −79.4 (d, J=6.5 Hz). ESLRMS m/z 419 (M−H). ESHRMS m/z 418.9559 (M−H, Calc'd 418.9523). Anal. Calc'd for C17H9Cl2F3O3S: C, 48.47; H, 2.15; Cl, 16.83; S, 7.61. Found: C, 48.38; H, 2.12; Cl, 17.09; S, 7.75.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[N:5]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[CH:15]=1)C(OC(C)(C)C)=O.C(Cl)[Cl:29]>>[ClH:29].[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[CH:15]=1
Reactant: ClCCl
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c(C)c1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)c(C)c1
Product: Cl
Yield: 96.6 %

Procedure:
N-BOC-4-amino-3-methylbenzoyl methionine methyl ester (0.99 g, 2.59 mmol) was dissolved in CH2Cl2 (15-20 ml) and precipitated with 3M HCl/Et2O (20.7 ml). 0.83 g (96.6%) of pale orange precipitate was obtained after drying overnight on the vacuum pump. mp 157°-159° C.; 1H NMR (CD3OD) 2.04 (3 H,s), 2.11-2.25 (1 H, m), 2.47 (3 H, s), 2.52-2.68 (3H. m), 3.74 (3 H, s), 4.75-4.80 (1 H, m), 7.48 (1 H, d, J=8.2 Hz), 7.81 (2 H, d, J=8.2 Hz), 7.87 (1 H, S); 13C NMR (CD3 0D) 15.23, 17.28, 31.43, 31.51, 52.91, 53.37, 124.41, 127.85, 131.99, 133.63, 134.14, 135.65, 169.05, 173.84; anal. calc. for C14H2N2 03S, C: 50.52, H: 6.36, N: 8.42; found C: 50.71, H: 6.40, N: 8.34.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17](=[O:25])[C:16]2=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.C(N(CC)C(C)C)(C)C>>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:34]=[CH:33][N:32]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](CCOCc3ccccc3)Nc3ncnc(N)c3C#N)n(-c3ccccc3)c(=O)c12
Yield: 69.1 %

Procedure:
(S)-2-(1-Amino-3-(benzyloxy)propyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (24 mg, 0.06 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (10 mg, 0.06 mmol), N,N-diisopropylethylamine (59 μl, 0.34 mmol) according to the method described in Example 17. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to obtain 21 mg (73% yield) of the title compound as a yellow solid. Purity 100%.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CCOCC>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.5 g 5-hexen-1-ol in 100 ml tetrahydrofuran is added 14 ml dihydropyran followed by 0.5 g p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 18 h and then diluted with ether. The mixture is then washed with saturated aqueous sodium bicarbonate, dried, filtered and evaporated. The resulting oil is chromatographed over silica gel using hexane/ether (18:1) as eluent to give 6-(2-tetrahydropyranyloxy)hex-1-ene; NMR (CDCl3): delta 5.85 (m,1H), 4.6 (brs,1H).
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=O)=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2.C(N(CC)CC)C.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[C:23]#[CH:24])[CH3:20].[CH3:28][NH:29][NH2:30]>O1CCOCC1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[S:1]1[C:5]([C:6]2[CH:24]=[C:23]([CH:22]([O:25][CH2:26][CH3:27])[O:21][CH2:19][CH3:20])[N:29]([CH3:28])[N:30]=2)=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2
Reactant: O=C(Cl)c1cc2c(s1)CCC2
Reactant: C#CC(OCC)OCC
Reactant: CNN
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cc(-c2cc3c(s2)CCC3)nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A solution of 5,6-dihydro-4H-cyclopenta[b]thiophene-2-carbonyl chloride (1.75 g, 9.36 mmol) in anhydrous dioxane (20 mL) was bubbled with argon for 10 minutes. Triethylamine (3.27 mL, 23.41 mmol) was added and the bubbling was maintained for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (219 mg, 0.31 mmol), copper iodide (119 mg, 0.62 mmol) and propargylaldehyde diethyl acetal (1.12 mL, 7.80 mmol) were added, and the reaction mixture was stirred for 2 hours at room temperature, under argon atmosphere. The solution was filtered and water (20 mL) was added to the filtrate. Layers were separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was added to a solution of methylhydrazine (0.82 mL, 15.6 mmol) in ethanol (80 mL). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo and dissolved in ethyl acetate (20 mL). The organic layer was successively washed with water (20 mL) and brine (20 mL) before being dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 90/10) to provide 3-{4H,5H,6H-cyclopenta[b]thiophen-2-yl}-5-(diethoxymethyl)-1-methyl-1H-pyrazole (37a) (1.80 g, 5.87 mmol, 75%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1>CN(C)C=O.CN(CN(C)C)C.C(Cl)(=O)C>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:11][N:12]([CH3:13])[CH3:6])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2
Agent: CN(C)CN(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CN(C)CCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-trifluoromethyl-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetramethyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N', N'-tetramethyldiaminomethane) are reacted together to give 8-trifluoromethyl-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.