Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]#[N:11].C(N)(=[S:14])C>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[S:14])[NH2:11]
Reactant: CC(N)=S
Reactant: Cn1c([N+](=O)[O-])cnc1C#N
Product: Cn1c([N+](=O)[O-])cnc1C(N)=S
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-methyl-5-nitro-2-cyanoimidazole (0.6mole) was dissolved in this mixture at 40° C. Thioacetamide (1.2 mole) was added and stirring continued for 3 hours at 40° C. The resultant solution was poured on to 4 liters of ice/water mixture and stirred for 30 minutes. The precipitate was collected, slurried with water, filtered and dried to yield 1-methyl-2-thiocarbamyl-5-nitroimidazole, m.p. 148°-50° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:23])[C@@H:10]([NH:15][C:16](OC(C)(C)C)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:5]1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O.[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([CH3:41])[C@H:36](C(O)=O)[CH3:37]>>[N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:23])[C@@H:10]([NH:15][C:16](=[O:17])[C@@H:36]([N:35]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH3:41])[CH3:37])[C:11]([CH3:12])([CH3:13])[CH3:14])[C@H:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C

Procedure:
The title compound of Example 1 was treated with trifluoroacetic acid using the general procedure A to deprotect the BOC group. The resulting trifluoroacetic acid salt was coupled to Boc-N-Me-Ala-OH using the general procedure D to prepare the title compound of Example 2. 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:31])[CH2:26][CH2:25]4)[CH2:21]3)=[O:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1[C:30]([N:27]1[CH2:28][CH2:29][N:24]([CH:22]2[CH2:23][N:20]([C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)=[O:19])[CH2:21]2)[CH2:25][CH2:26]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.9 %

Procedure:
To a solution of compound 17c (826 mg, 1.61 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was extracted with CH2Cl2, and H2O after basifying the water layer to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 916 (675 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.3Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.54 (br. s., 1H), 4.44 (br. s., 1H), 4.01-4.35 (m, 6H), 3.75-3.95 (m, 2H), 3.12-3.31 (m, 2H), 2.85 (t, J=5.8 Hz, 1H), 2.49 (br. s., 4H). MS m/z (M+H+) 412.0.
Reaction SMILES: I[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].C1COCC1>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.C(N(CC)CC)C>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:34]#[C:33][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CSc1ncc(C(F)(F)F)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(SC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
4-Iodo-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I12) (2.00 g, 6.24 mmol), PdCl2(PPh3)2 (438 mg, 625 μmol), CuI (119 mg, 625 μmol) and triphenylphosphine (164 mg, 625 μmol) were placed into an oven dried microwave reaction vial under nitrogen. Methyl 2-(2-ethynylphenyl)acetate (I4) (1.31 g, 7.49 mmol), THF (20 mL) and triethylamine (10 mL) were added and the resulting mixture was stirred at 100° C. under microwave irradiation for 10 min. The volatiles were evaporated under reduced pressure then the residue was adsorbed onto silica from DCM. The pre-adsorbed material was chromatographed on silica gel (6-25% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I13) (1.571 g, 69%) as an orange solid; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=0.8 Hz, 1H), 7.68 (dd, J=7.7, 1.1 Hz, 1H), 7.50-7.29 (m, 3H), 3.93 (s, 2H), 3.71 (d, J=3.4 Hz, 3H), 2.62 (d, J=3.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH2:24]([NH:28][C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCNc1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12

Procedure:
A mixture of of 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine in toluene (2 mL) and excess of butylamine (1 mL) in sealed tube was heated at 110° C. for overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give N-butyl-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-α]pyridin-7-amine. 1H NMR (CDCl3): δ 8.53 (d, 2H, J=5.1 Hz), 7.54–7.57 (m, 2H), 7.20–7.24 (m, 3H), 7.06 (t, 2H, J=8.6 Hz), 7.02–7.00 (m, 1H), 6.04 (bs, 1H), 5.95 (d, 1H, J=7.7 Hz), 3.39 (q, 2H, J=6.4 Hz), 1.74–1.78 (m, 2H), 1.47–1.56 (m, 2H), 0.99 (t, 3H, J=7.4 Hz); MS m/z 361 (M+1).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=1.[SH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(OCC)(=O)C>CN(C)C=O>[C:20]([O:19][C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH2:9][S:24][C:25]2[C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=[CH:32][N:33]=2)[CH:15]=[CH:14][N:13]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1cccnc1S
Reactant: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(CSc2ncccc2C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
A solution of triethylamine (0.75 mL, 5.4 mmol) in N,N-dimethylformamide (2.0 mL) was added to a solution of 4-bromomethyl-2-tert-butoxycarbonylaminopyridine (Reference compound No. 8-1, 500 mg, 1.7 mmol) and 2-mercaptonicotinic acid (270 mg, 1.7 mmol) in N,N-dimethylformamide (3.0 mL) under ice-cooling, and the mixture was stirred for 12 hours at room temperature. Ethyl acetate (20 mL) was added to the reaction mixture, and the whole was extracted with 0.1N aqueous sodium hydroxide solution (50 mL). 1N Hydrochloric acid was added to the aqueous layer to adjust to pH 5, and the precipitated crystal was filtered off. The crystal was dried under reduced pressure at 60° C. to give 560 mg of the title reference compound as a colorless crystal. (Yield 88%)
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([Br:12])[C:3]=1C=O.[OH:13]O>[OH-].[Na+]>[Br:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[C:3]=1[OH:13]
Reactant: OO
Reactant: COc1ccc(Br)c(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Br)c(O)c1O
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Aldehyde 12 (23 g) was suspended in 2% sodium hydroxide (300 mL) and a solution of 30% hydrogen peroxide (15.8 g, 1.4 eq.) was added. After 2 hours, another portion of 30% hydrogen peroxide (1.4 eq.) was added and the solution stirred overnight. The reaction mixture was acidified, extracted with dichloromethane, washed with sodium thiosulfate and the solvent removed in vacuo to afford a tan solid. The solid was recrystallized from methanol to afford colorless crystals (14 g, 64%): m.p. 122.3-124.3° C., lit20 m.p. 124-126° C.; EIMS m/z 220 (M+, 81Br), 218 (M+, 79Br), 205, 203, 177, 175, 95; 1HNMR δ 6.99 (1H, d, J=9.0 Hz, H5), 6.42 (1H, d, J=9.0 Hz, H4), 5.56 (1H, s, OH), 5.51 (1H, s, OH), 3.88 (3H, s, OCH3); 13C—NMR (75.5 MHZ) δ 146.59, 140.95, 133.47, 122.21, 104.35, 101.55, 56.31; Anal. Calcd. For C7H7O3Br: C, 38.39; H, 3.22. Found: C, 38.47; H, 3.36.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11](O)([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:39])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:39])([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(CN2CCOCC2)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN2CCOCC2)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (85 mg, 0.18 mmol) in CH2Cl2 (10 mL) under N2 atmosphere at −78° C. was added DAST (47 μL, 0.359 mmol). The reaction mixture was then allowed to reach RT and further stirred for 1.5 h then poured into an aqueous saturated solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 8:2) to give the desired material. MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M−H]−; tR (HPLC conditions f): 1.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N+:22]([O-])=O)[C:3]=1[CH3:25].O>C(O)(=O)C.[Fe]>[NH2:22][C:4]1[C:3]([CH3:25])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(4-Chloro-6-fluoro-3-methyl-2-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.2 mmol) was dissolved in acetic acid (20 ml) and iron powder (1.2 g, 21.5 mmol) was added. Solution was stirred at ambient temperature for 14 hr. Water was added and product extracted with ethyl acetate followed by evaporation under reduced pressure. Title compound was separated by column chromatography on silica gel (eluent, hexane-ethyl acetate, 7:3; 1.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:16])=[O:15].CO[C:19]([C@H:21]1[C@H:25]([CH3:26])[CH2:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22]1)=O>>[CH2:27]([N:23]1[CH2:24][C@@H:25]([CH3:26])[C@H:21]([C:19]2[NH:16][C:14](=[O:15])[C:3]3[C:4]([CH3:13])=[N:5][N:6]([CH:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1nn(C2CCOCC2)c(N)c1C(N)=O
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Product: Cc1nn(C2CCOCC2)c2nc([C@@H]3CN(Cc4ccccc4)C[C@H]3C)[nH]c(=O)c12

Procedure:
Following the procedure for the preparation of 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-amino-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide and (3S,4S)-methyl-1-benzyl-4-methylpyrrolidine-3-carboxylate provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.51-7.30 (m, 5H), 4.75-4.68 (m, 1H), 4.13-4.08 (m, 2H), 3.84-3.73 (m,1H), 3.63-3.48 (m, 2H), 3.40 (m,1 H), 3.10-2.78 (m, 2H), 2.55 (s, 3H), 2.50-2.24 (m, 3H), 1.87-1.80 (m, 2H), 0.61-1.41 (m, 3H), 1.19 (d, J=6.6 Hz, 3H). MS: (M+H m/z=408.1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:9][CH:8]=3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(Cc2ccc(N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COC(=O)c1ccc(Cc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 37.9 %

Procedure:
Using general procedure A, 4-(4-amino-benzyl)-benzoic acid methyl ester (0.66 g, 2.7 mmol) and 1-Boc-4-piperidone (545 mg, 2.74 mmol) gave 4-[4-(4-methoxycarbonyl-benzyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (434 mg, 36%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[S].[C:13](=[S:15])=[S:14]>>[C:1]([C:5]1[CH:11]=[CH:10][C:9]2[S:14][C:13]([SH:15])=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: S=C=S
Agent: [S]
Product: CC(C)(C)c1ccc2sc(S)nc2c1
Yield: 88.3 %

Procedure:
In a autoclave of 3 liters, 1341g of meta-tert-butylaniline, 820g of carbon disulfide and 288g of sulfur were placed, the reaction was carried out under the same conditions as above. After cooling, 1765g of 5-tert-butyl-(2-mercapto)benzothiazole was obtained. (yield: 88.3%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1.ClC1C=C(C=CC=1)C(O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:10]3=[N+:11]([O-:33])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+]([O-])c32)CC1
Reaction time: 1.58 h
Yield: 51.8 %

Procedure:
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5 g, 13.06 mmol) was dissolved in CH2Cl2 at −10° C. 3-Chlorobenzoic acid(4.9 g, 15.67 mmmol) was then added and the reaction mixture stirred for 95 minutes. The reaction mixture was taken up in CH2Cl2 and extracted with sodium bisulfite, 10% NaOH. The crude reaction product was purified on silica gel eluting first with 1% and then with 2% MeOH in CH2Cl2 to give the title compound (2.7 g, MH+ 399).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=O.[CH3:22][NH:23][NH2:24]>C(O)C>[O:13]=[C:7]1[CH2:8][CH2:9][CH2:10][C:11]2[N:23]([CH3:22])[N:24]=[C:4]([C:3]3[CH:14]=[CH:15][C:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:17][C:2]=3[Cl:1])[C:6]1=2
Reactant: CNN
Reactant: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Solvent: CCO
Product: Cn1nc(-c2ccc(S(C)(=O)=O)cc2Cl)c2c1CCCC2=O

Procedure:
2 g of 2-(2-chloro-4-methanesulfonylbenzoyl)cyclohexane-1,3-dione are dissolved in 50 ml of ethanol, 0.28 g of methylhydrazine are added, and the solution is then refluxed for 4 hours. It is subsequently allowed to cool, and the precipitate which has separated out is filtered off with suction. 0.85 g (41% of theory) of the desired product of the formula ##STR9## of melting point 208° C. is obtained.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[CH2:20]([NH:27][C:28]([C:30]1[S:34][C:33]([N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])=[N:32][C:31]=1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([C:30]1[S:34][C:33]([N:35]2[CH2:39][CH2:38][N:37]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:36]2=[O:40])=[N:32][C:31]=1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: Fc1cccc(CBr)c1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3cccc(F)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 8 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 1-(bromomethyl)-3-fluorobenzene to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 8% yield: mp 155-156° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 6H), 7.06-6.96 (m, 3H), 5.87 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 4.45 (s, 2H), 4.10-4.05 (m, 2H), 3.49-3.43 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.8, 155.5, 151.4, 140.1, 136.7, 129.1, 128.7, 128.2, 127.9, 127.6, 127.1, 118.2, 47.3, 43.0, 42.4, 42.0, 17.5; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Br[CH2:13][C:14]([O:16][CH2:17]C)=[O:15]>[Li+].C[Si]([N-][Si](C)(C)C)(C)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])[C:6]1=[O:11]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)CC1Cc2c(Br)cccc2C1=O
Temperature: 0 °C
Yield: 91.8 %

Procedure:
To a solution of 4-bromoindanone (15.8 g, 75 mmol) at −78° C. was added LiHMDS (1 M in THF, 90 mL). The slight brown solution was allowed to warm up to 0° C., and was cooled again to −75° and ethyl 2-bromoacetate (9.1 mL, 82 mmol) was added dropwise. The mixture was allowed to warm up over night (−75° C. to −20° C. over 12 h). The mixture was quenched with sat. ammonium chloride and was extracted with ethyl acetate. Flash chromatography give 19.5 g of the title compound in a mixture with the starting indanone ethyl 2-[4-bromo-2-(2-ethoxy-2-oxo-ethyl)-1-oxo-indan-2-yl]acetate H9 and which was used without further purification for the next step (purity, 60% of the desired product).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4].Cl[C:14]1[C:23]2[C:18](=[C:19]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:32])[CH:15]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:11])([F:10])[F:12])[C:3]=1[NH:4][C:14]1[C:23]2[C:18](=[C:19]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:32])[CH:15]=1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: Nc1c(Cl)cccc1C(F)(F)F
Product: COc1ccc2c(Nc3c(Cl)cccc3C(F)(F)F)cc(=O)oc2c1OC1CCCC1

Procedure:
The title compound was prepared from 2-chloro-6-(trifluoromethyl)aniline and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16. 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.05 (d, 1H), 7.93 (d, 1H), 7.91 (d, 1H), 7.71 (t, 1H), 7.18 (d, 1H), 4.82 (m, 1H), 4.29 (s, 1H), 3.90 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 453.9.
Reaction SMILES: C(OC1C(=O)C=[CH:12][N:11](CC(F)(F)F)[CH:10]=1)C1C=CC=CC=1.Cl.Cl[CH:23]([C:28]1[C:29](=[O:37])[C:30]([OH:36])=[C:31]([CH3:35])[N:32]([CH3:34])[CH:33]=1)[C:24]([F:27])([F:26])[F:25].CNC.O>ClCCl.CO.ClCCl.C(#N)C>[CH3:10][N:11]([CH3:12])[CH:23]([C:28]1[C:29](=[O:37])[C:30]([OH:36])=[C:31]([CH3:35])[N:32]([CH3:34])[CH:33]=1)[C:24]([F:27])([F:26])[F:25]
Reactant: O=c1ccn(CC(F)(F)F)cc1OCc1ccccc1
Reactant: Cc1c(O)c(=O)c(C(Cl)C(F)(F)F)cn1C
Agent: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(O)c(=O)c(C(N(C)C)C(F)(F)F)cn1C
Yield: 56 %

Procedure:
Thionyl chloride (7.5 mL, 102.7 mmol) was added dropwise to a suspension of 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (3.00 g, 12.7 mmol) and acetonitrile (110 mL) with external cooling using a tap water bath under a blanket of nitrogen. The progress of the reaction was monitored by TLC (eluant: methanol:dichloromethane, 1:10, v:v). After the addition of SOCl2, a clear solution resulted, and white solid gradually formed upon further stirring. The reaction mixture was concentrated repeatedly in acetonitrile to give a solid, which was then collected and washed with acetonitrile (15 mL×2). Thus, 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride, was obtained as a white solid (2.89 g). Yield=78%; 1H NMR (DMSO-D6) δ (ppm): 8.17 (s, 1H), 6.19 (q, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.35 (s, 3H). (c) A mixture of 5-(1-chloro-2,2,2-trifluoroethyl)-3-hydroxy-1,2-dimethylpyridin-4(1H)-one hydrochloride (395 mg, 1.4 mmol) and acetonitrile (30 mL) was added to a 40 wt % dimethylamine in water (3.5 mL, 27.7 mmol). The resulting yellowish solution was stirred vigorously, and the progress of the reaction was monitored by TLC (eluant: methanol/dichloromethane, 1/10, v/v). The starting material was completely consumed within 5 min. The reaction mixture was concentrated to give a solid. The solid was dissolved in dichloromethane (30 mL), which was then washed with a 10% ammonium chloride solution (15 mL×2). The organic phase was dried over sodium sulfate, filtered, and concentrated to give 5-[1-(dimethylamino)-2,2,2-trifluoroethyl]-3-hydroxy-1,2-dimethylpyridin-4(1H)-one (Apo7053) as a solid product (200 mg). Yield=56%; HPLC Method 1, RT=10.2 min, HPLC purity (AUC): 98.3% at 280 nm); 1H NMR (DMSO-D6) δ (ppm): 7.68 (s, 1H), 4.86 (q, J=10.1 Hz, 1H), 3.73 (s, 3H), 2.29 (s, 3H), 2.23 (s, 6H). MS-ESI m/z 265 [M+1]+, 220 (100%), 192.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25].[H][H]>[Pd].N1C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(C#Cc4ccccc4)cc3CC[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4ccccc4)cc3CC[C@@H]12

Procedure:
A 300 mg portion of the product of Example 284 was hydrogenated over palladium/barium sulfate catalyst in 25 mL of pyridine at 15 psi hydrogen pressure at ambient temperature for 1 h. The mixture was then filtered and concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with 75% ethyl acetate/hexane. The product thereby obtained was further purified on a Chromatatron, eluting with 5% isopropanol in chloroform to obtain the desired product in the form of a yellow oil. High resolution mass spectroscopy showed the correct molecular ion of 332.201440.