Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH:22]=[C:23]([F:25])[F:24])[CH:16]=[CH:17][C:7]2=1.[Br:34]N1C(=O)CCC1=O>C(#N)C>[Br:34][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:21][CH:22]=[C:23]([F:25])[F:24])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC=C(F)F)NC(=O)OC(C)(C)C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC=C(F)F)NC(=O)OC(C)(C)C)c(Br)cc21
Temperature: 80 °C
Yield: 67.4 %

Procedure:
A solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5-difluoropent-4-en-2-yl)carbamate (1.03 g, 2.24 mmol) in acetonitrile (22 mL) was treated with N-bromosuccinimide (0.44 g, 2.5 mmol), heated to 80° C. for 45 min, and then concentrated under reduced pressure. The crude material was purified over SiO2 (1-4% 2M ammonia in methanol/dichloromethane gradient elution) to afford (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5-difluoropent-4-en-2-yl)carbamate (0.81 g, 1.51 mmol, 67% yield) as a white solid. LC/MS, (ESI) m/z 537.9 [(M+H)+, calcd for C24H27BrF2N3O4, 538.1]; 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (d, J=5.8 Hz, 1H), 8.22 (s, 1H), 7.65 (d, J=5.5 Hz, 1H), 6.75 (s, 1H), 5.01 (d, J=8.3 Hz, 1H), 4.41-4.26 (m, 1H), 4.24-4.04 (m, 3H), 3.67 (s, 3H), 3.12 (s, 3H), 2.64-2.34 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:37])([F:36])[F:38])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3OC(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.28 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.038 g, 0.071 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.034 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.35 (d, J=7.82 Hz, 1 H) 8.06 (d, J=7.82 Hz, 2 H) 7.97-8.03 (m, 1 H) 7.91 (br. s., 2 H) 7.74 (t, J=7.90 Hz, 1 H) 7.59-7.67 (m, 1 H) 7.55 (d, J=7.82 Hz, 2 H) 7.38 (t, J=8.20 Hz, 1 H) 6.60 (d, J=10.80 Hz, 1 H) 3.84 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C26H17F4O5S [(M−H)−] 517, obsd. 517.3.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][NH:24][CH:25]([CH3:27])[CH3:26]>CS(C)=O>[CH3:22][C:3]1[C:2]([N:24]([CH3:23])[CH:25]([CH3:27])[CH3:26])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CNC(C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N(C)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), N-methylpropan-2-amine (29.6 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-(methyl(1-methylethyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 11.87 (br. s, 1H), 7.86-7.93 (m, 1H), 7.59-7.68 (m, 1H), 7.39-7.50 (m, 1H), 7.17 (s, 1H), 6.95 (br. s, 1H), 4.16-4.28 (m, 1H), 3.38-3.46 (m, 2H), 2.82-2.89 (m, 2H), 2.66 (s, 3H), 2.55 (s, 3H), 1.22-1.28 (m, 6H). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C@H:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][C@H:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: C[C@@H](O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 68.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide (78 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl-amino)-1H-benzoimidazole-5-carboxylic acid (100 mg), (R)-(−)-1-amino-2-propanol (20 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.86-7.65 (m, 2H), 7.48 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.89-3.77 (m, 1H), 3.64 (bs, 3H), 3.26-3.19 (m, 2H), 1.09 (d, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][N:18]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[Na+].C(O)(=O)C>C(O)(C)C>[CH:21]1([C:20]2[C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][C:9]([C:11]4[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=4)=[N:8][C:7]=3[N:18]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:19]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (11.3 g) and sodium hydroxide solution (1N, 100 mL) in isopropanol (100 mL) was stirred at r.t. for 5 h. The mixture was poured onto ice-water and the pH was adjusted to 5 with acetic acid. The mixture was extracted with dichloromethane three times and the combined organic layers were dried over magnesium sulphate, filtrated and concentrated in vacuo. 10.35 g (95%) of the title compound were obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CN1CC[O:35][CH2:34][CH2:33]1.C(OC(=O)C)(=O)C>ClCCl>[C:34]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:35])[CH3:33]
Reactant: NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Reactant: CN1CCOCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
150 mg of (2E)-3-(1-amino-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethyl}acrylamide were dissolved in 5 ml of dichloromethane, admixed with 71 mg of N-methylmorpholine and 36 mg of acetic anhydride, and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator to obtain 165 mg of (2E)-3-(1-acetamido-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide (100%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[N:23]1([CH2:29][CH:30]([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[C:3]([C:12]([N:26]2[CH2:25][CH2:24][N:23]([CH2:29][CH:30]([N:34]3[CH:38]=[C:37]([C:39]4[C:40]5[CH:47]=[CH:46][NH:45][C:41]=5[N:42]=[CH:43][N:44]=4)[CH:36]=[N:35]3)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27]2)=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCC(CN1CCN(C(=O)c2ncc(C(F)(F)F)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0000426 mol) was added to a solution of 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (11 mg, 0.053 mmol) and triethylamine (30 microL, 0.21 mmol) in THF (0.4 mL). After stirring for 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (9 mg, 48%). 1H NMR (300 MHz, d6-dmso): δ □8.88 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.48 (dd, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.67-3.56 (m, 2H), 3.25-3.12 (m, 4H), 2.92-2.79 (m, 2H), 2.66-2.55 (m, 1H), 2.55-2.38 (m 2H), 2.38-2.25 (m, 1H); LCMS (M+H)+: 528.3.
Reaction SMILES: C1(C)C=CC(S(OCC[C@:13]2([OH:27])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18](F)[CH:19]=3)[C@H:14]2C(C)C)(=O)=O)=CC=1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[OH:27]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)CCc3cc(F)ccc3[C@H]2C(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Oc1ccc2ccccc2c1

Procedure:
A solution of 12.6 g (0.031 mol) of [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethyl p-toluenesulphonate, 6.1 g (0.031 mol) of 3,4-(methylenedioxy)-N-methyl-β-phenethylamine and 5.3 ml (0.031 mol) of ethyldiisopropylamine in 50 ml of dimethyl sulfoxide was stirred under a nitrogen atmosphere for 3 hours at 80° and thereafter concentrated in a high vacuum. The residue was dissolved in methylene chloride and the solution obtained was washed with a saturated sodium carbonate solution and extracted three times with 3N hydrochloric acid. The aqueous extracts were made alkaline with a 28% sodium hydroxide solution. The oily suspension was extracted three times with methylene chloride. The organic extracts were dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel with ethyl acetate/methanol (9:1), yielding 9.3 g (73%) of [1R,2R]-(-)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-[[3,4-(methylenedioxy)phenethyl]methylamino]ethyl]-2-naphthalenol as a yellowish oil; [α]D20 =-22.1°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Cl.Cl[CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][CH2:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][N:27]=1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Reactant: Cn1ncnc1CCl
Agent: Cl
Product: Cn1ncnc1COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 58.6 %

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with 5-chloromethyl-1-methyl-1H-[1,2,4]triazole hydrochloride (prepared as described in WO 0023449, 30.4 mg, 0.20 mmol) as described in Example 47, affording 5-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-2-trifluoromethyl-[1,8]naphthyridine (37.8 mg, 58%). δH (360 MHz, CDCl3) 4.06 (3H, s), 5.39 (2H, s), 7.08-7.12 (1H, m), 7.28-7.36 (2H, m), 7.51 (1H, d, J 4.2), 7.82 (1H, d, J 8.8), 7.87 (1H, s), 8.43 (1H, d, J 8.4), 9.27 (1H, d, J 4.6). m/z (ES+) 404 [MH]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1cc[nH]c1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cc[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (1H-pyrrol-3-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil. LC/MS (Method B) 2.66 min, [M+1]+ 460. Potency class ND.
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1.[CH2:26](N(CC)CC)[CH3:27].C([Si](C)(C)C)#C>C(#N)C.CC(O)=O.CC(O)=O.[Pd]>[C:26]([C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1)#[CH:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)ccc(OC)c21
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: C#C[Si](C)(C)C
Solvent: CC(=O)O
Solvent: CC#N
Product: C#Cc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: 50 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 50 mg (0.111 mmol) 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 0.1 ml (0.77 mmol) triethylamine, 0.1 ml (0.7 mmol) ethinyltrimethylsilane and 5 mg palladium-II-acetate in 1 ml acetonitrile is stirred at 50° C. for 3 hours. Then the reaction mixture is cooled to room temperature and poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 17 mg of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:33])([F:32])[CH:17]([OH:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:31][CH:17]([C:16]([F:15])([F:32])[F:33])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F)c1ccc(Cl)cc1
Yield: 98.3 %

Procedure:
This compound was prepared in the manner of Example II, using 5.3 g of 2-(4-chlorophenyl)-3-methylbutanoyl chloride, whose preparation is described in Agr. Biol. Chem., 31, 1148 (1967), together with J. Kagaku To Seibutsu, 14, 427 (1976), 4.6 g of α-trifluoromethyl-3-phenoxybenzyl alcohol, and 1.5 g of pyridine in 50 ml of toluene. Volatiles were removed from the crude reaction product at 100° C./0.02 mm through a short path Kugelrohr distillation system to give as a residue 7.8 g of α-trifluoromethyl-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanoate. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1>[Pd]>[NH:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:12]1
Reactant: O=C(O)C=CC1CN(C(=O)OCc2ccccc2)CCO1
Agent: [Pd]
Product: O=C(O)CCC1CNCCO1
Yield: 69.8 %

Procedure:
3-(4-((benzyloxy)carbonyl)morpholin-2-yl)acrylic acid (0.52 g, 1.8 mmol) was reacted with Pd—C (10%, 0.05 g) according to the procedure as described in Example 34, Step C to give the title compound as a white solid (0.2 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1C=CC=CC=1.O>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc(F)cc1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]-hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 6.3 g. portion of p-fluorobenzoyl chloride in 40 ml. of benzene is added and the mixture is stirred overnight. The solid in the aqueous layer is recovered by filtration, washed with water and slurried in ether giving the product as white crystals, mp 101°-103° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1COCC1>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][C:18]=1[C:24]([F:27])([F:25])[F:26])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1ccc(F)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2ccc(F)cc2C(F)(F)F)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a room temperature solution of (0.7 g, 3.55 mmol) of 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione and THF (30 mL) was added (0.73 g, 3.78 mmol) of the 4-fluoro-2-trifluoromethylbenzylamine via a syringe. The resulting mixture was stirred at room temperature for 12 hours. After concentration in vacuo, the resulting white solid was recrystallized from hot acetonitrile to give 0.55 gm (52%) of 3-tert-butylamino-4-(4-fluoro-2-trifluoromethyl-benzylamino)-cyclobut-3-ene-1,2-dione as a white solid: mp 192°-194° C.; 1H NMR (DMSO-d6) δ1.36 (s, 9H), 4.88 (d, 2H) 7.67 (m, 5H) ppm; IR (KBr) 3250, 2900, 1800, 1580, 1530 cm-1 ; MS (m/z) 345 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:21]([CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2)([OH:23])=[O:22]>>[C:21]([CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]1=[O:17])[CH:29]=[CH:28]2)([OH:23])=[O:22]
Reactant: O=C(O)Cc1ccc2[nH]ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Product: O=C(O)Cc1ccc2c(ccn2Cc2cccc(CN3C(=O)c4ccccc4C3=O)c2)c1

Procedure:
This compound was prepared in a manner analogous to Example 14a) starting from 2-(3-bromomethyl-benzyl)-isoindol-1,3-dione and 5-carboxymethyl-indole.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][C:4]=1[Cl:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[S:7][C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[C:4]([Cl:9])[N:5]=1
Reactant: Clc1nc(Cl)c(CBr)s1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2sc(Cl)nc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 5-(bromomethyl)-2,4-dichloro-1,3-thiazole, 6-methyl-2-sulfanylpyrimidin-4-ol (500 mg, 3.5 mmol), and triethylamine (2.5 mL, 18.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (778 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.46 (s, 2H), 6.09 (s (br), 1H); M+ 310.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][O:25][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(COC(=O)C(C)(C)C)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (0.48 mmol) of compound 3-(4-fluorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from Example 63 are dissolved in 3 ml of pyridine. 294 μl (2.38 mmol) of pivaloyl chloride are added and the mixture is then stirred at ambient temperature for 2 hours. H2O is added, the mixture is extracted with EtOAc, the organic phase is washed with a saturated NH4Cl solution and then dried over MgSO4, and the product is filtered and concentrated. Purification is carried out by chromatography on a silica gel column, elution being carried out with EtOAc.