Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:15]([N:17]1[CH2:63][CH2:62][CH2:61][C@H:18]1[C:19]([N:21]1[CH2:60][CH2:59][CH2:58][C@H:22]1[C:23]([NH:25][C@H:26]([C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[O:53])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:51])[NH:32][S:33]([C:36]1[C:49]([CH3:50])=[C:47]([CH3:48])[C:46]2[O:45][C:42]([CH3:44])([CH3:43])[CH2:41][CH2:40][C:39]=2[C:37]=1[CH3:38])(=[O:35])=[O:34])=[O:24])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:64]([C:76]([O:78][CH2:79][CH:80]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[C:86]2[C:81]1=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:77])[C@H:65]([C:73](O)=[O:74])[C@@H:66]([CH3:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH:64]([C:76]([O:78][CH2:79][CH:80]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[C:86]2[C:81]1=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:77])[C@H:65]([C:73]([NH:1][C@H:2]([C:15]([N:17]1[CH2:63][CH2:62][CH2:61][C@H:18]1[C:19]([N:21]1[CH2:60][CH2:59][CH2:58][C@H:22]1[C:23]([NH:25][C@H:26]([C:52]([C:54]([CH3:55])([CH3:57])[CH3:56])=[O:53])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:51])[NH:32][S:33]([C:36]1[C:49]([CH3:50])=[C:47]([CH3:48])[C:46]2[O:45][C:42]([CH3:43])([CH3:44])[CH2:41][CH2:40][C:39]=2[C:37]=1[CH3:38])(=[O:35])=[O:34])=[O:24])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[O:74])[C@@H:66]([CH3:72])[O:67][C:68]([CH3:70])([CH3:71])[CH3:69]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](C)OC(C)(C)C)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
H-Lys(Boc)-Pro-Pro-Arg(Pmc)-t-Bu (3.55 g, 3.86 m mmol) was added to a solution of the activated acid prepared from Fmoc-Thr(t-Bu)-OH (1.6 g, 4 mmol) and HATU (1.9 g, 5 mmol) and DIEA (1.29 g, 10 mmol) in dry CH2Cl2 (25 mL) and stirred for 20 h at RT. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with saturated sodium carbonate (2×200 mL), water (2×200 mL) and dried (sodium sulfate). The solution was filtered and the solvents were removed under reduced pressure to leave behind a paste. The paste was chromatographed over flash silica gel (400 g). Elution with 2% methanol in chloroform furnished the product as a colorless foam. Yield: 3.5 g (70%). m.p. 135-138° C. MS m/z 1298.2 [M+H].
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:19]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[CH2:17][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 84A. mp 113-115° C.; HPLC: area %=97.30, r.t.=3.140 min, γ=214 nm, mobile phase=acetonitrile/water w/0.10% TFA; IR (KBr) cm−1: 2952, 2577, 1742, 1582, 1323, 1120; 400 MHz 1H NMR (DMSO-d6): δ 87.67-7.74 (m, 2H), 7.56-7.63 (m, 2H); 7.13 (t, 1H, J=7.8 Hz), 6.76-6.93 (m, 4H), 6.22 (d, 1H, J=8.7 Hz), 5.08 (s, 2H), 4.45 (s, 2H), 4.08 (t, 2H, J=4.8 Hz), 3.91 (s, 2H), 2.54 (t, 2H, J=6.6 Hz), 1.82 (pentet, 2H); MS m/z 505 (M+1). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60. found: C, 61.49; H, 4.44.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1.CO.[CH2:25](Cl)Cl>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:25][C@H:11]2[C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:19]2)=[O:13])=[CH:6][CH:5]=1
Reactant: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccc(F)cc2)CC1
Reaction time: 0.05 h
Yield: 57 %

Procedure:
To a vigorously stirring mixture of NaH (300 mg, 12.5 mmol) in DMSO (30 mL) at ambient temperature under an argon (g) atmosphere was added (CH3)3S(I)O (2.50 g, 11.4 mmol) in small portions over 1 min. Following complete addition, the reaction was stirred for 50 min before the rapid dropwise addition of DMSO (10 mL) solution of 10A (1.57 g, 5.68 mmol). After ca. 50 h the reaction was quenched with H2O (80 mL) and extracted into EtOAc (75 mL). The phases were separated and the aq. phase was further extracted with EtOAc (2×70 mL). The combined organics were washed with H2O (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting gum was subjected to flash chromatography (SiO2—40 g; gradient elution: 1% MeOH/DCM for 3 min then 1%-5% MeOH/DCM over 20 min at 40 mL/min) to afford 947 mg 10B (57% yield). m/z (ES+) M+1=291.3; HPLC tR=1.52 min. 1H NMR (500 MHz, CDCl3) δ 7.07 (dd, J=8.7, 5.3 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H), 3.63 (dd, J=14.5, 5.0 Hz, 4H), 2.71 (ddd, J=13.0, 6.7, 6.6 Hz, 1H), 2.57-2.44 (m, 4H), 1.90 (ddd, J=8.3, 5.4, 4.3 Hz, 1H), 1.68-1.56 (m, 2H), 1.21 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 1.04 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.[CH:30]1([C:36](=[S:38])[NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:38][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:37][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: NC(=S)C1CCCCC1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCCCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Yield: 66 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.45 g, 1.019 mmol) and cyclohexanecarbothioamide (0.18 mg, 1.23 mmol) the title compound of Step B was obtained (0.38 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 7.61-7.75 (m, 1H), 7.39-7.50 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.86 (d, J=5.3 Hz, 1H), 2.96-3.12 (m, 1H), 2.09 (d, J=10.6 Hz, 2H), 1.78 (dd, J=9.7, 3.2 Hz, 2H), 1.68 (d, J=12.5 Hz, 1H), 1.47-1.61 (m, 2H), 1.33-1.45 (m, 2H), 1.21-1.32 (m, 1H). m/z (ES+): 566 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[S:13].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]=[C:12]1[SH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: NCCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: SC1=NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Solutions of 10.9 g (0.067 mol) N-benzylethylenediamine (Example 2) and 7.65 g (0.067 mol) thiophosgene, each dissolved in 50 ml toluene, were added dropwise and concurrently to a stirred mixture of 14.1 g (0.133 mol) sodium carbonate dissolved in 100 ml water and 100 ml toluene which had been chilled to 0° C. After the 20-30 minute addition period the reaction mixture was allowed to warm to ambient temperature and stirring was continued at this temperature for one hour. The reaction mixture was filtered and the insoluble solid, 7.2 g, was recrystallized twice from methanol-ethyl acetate to give 2.25 g (18% yield) of desired product, m.p. 177°-182° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[SH:11][CH2:12][C:13]([O:15]CC)=[O:14].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:12]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:13].[SH:11][CH2:12][C:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1ncccc1[N+](=O)[O-]
Product: O=C([O-])CS
Yield: 127.4 %

Procedure:
A solution of 50 g of 3-nitro-2-chloropyridine and 38 g of ethyl mercaptoacetate in 400 ml of ethanol containing 30 g of sodium bicarbonate is heated under reflux for 7 hours. The solution is subsequently concentrated in vacuo and then, after cooling, the residue is treated with water and ice and extracted with ether. The ether phase is washed with water and dried, the solvent is evaporated off and a residue is recovered which crystallizes from isopropyl ether. The crystals are filtered off and dried to give 49 g of ethyl 3-nitropyridine-2-mercaptoacetate in the form of crystals of melting point 58° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]([O:14]CC)=[O:13])=[N:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[N:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ncc(Cn2ccnc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ncc(Cn2ccnc2)s1

Procedure:
A solution of ethyl 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylate (143 mg, 0.60 mmol) and 1 M LiOH solution (1.2 ml, 1.2 mmol) in THF (2 ml) and MeOH (1 ml) was stirred at RT for 1.5 h. Some 1 M HCl was added until pH of the mixture was about 8. Solvents were evaporated and thus obtained crude product was used as such in the next synthesis step. 1H-NMR (400 MHz; d6-DMSO): δ 5.28 (s, 2H), 6.92 (s, 1H), 7.22 (s, 1H), 7.54 (s, 1H), 7.79 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:49][CH:50]1[CH2:53][NH:52][CH2:51]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:52]3[CH2:53][CH:50]([OH:49])[CH2:51]3)[CH:31]=[CH:30][CH:29]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(-c2nc(-c3ccc(C4CCOCC4)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C4CCOCC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.313 mmol) of the compound from Example 4A and 146 mg (0.469 mmol) of the compound from Example 8A were used to obtain 77 mg (52% of theory) of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][C:58]1=[O:63].C(Cl)[Cl:65]>>[ClH:65].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][O:60][CH2:59][C:58]4=[O:63])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: O=C1COCCN1CCO
Reactant: ClCCl
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCN1CCOCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26 %

Procedure:
Diethyl azodicarboxylate (368 μl, 2.34 mmol) was added dropwise to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (284 mg, 0.78 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (613 mg, 2.34 mmol) and 4-(2-hydroxyethyl)-3-morpholinone (170 mg, 1.17 mmol), (EP580402A2), in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 2.5 hours at ambient temperature, the insolubles were removed by filtration. The filtrate was purified by pouring it directly on to a column of silica and eluting with methylene chloride/ethyl acetate/methanol (60/35/5). The purified product was triturated with ether and collected by filtration. The solid was dissolved in methylene chloride containing a few drops of methanol and 3.8M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration and dried under vacuum to give of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(3oxomorpholino)ethoxy)quinazoline hydrochloride (108 mg, 26%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[CH2:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][NH:27]1>>[ClH:1].[ClH:1].[CH2:22]([CH:21]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:28][CH2:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:26]4)=[CH:4][CH:5]=3)[O:13][N:12]=2)[CH2:16][CH2:17]1)[CH2:24][CH3:25])[CH3:23]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCC(CC)N1CCC(Cc2noc(-c3ccc(CCl)cc3)n2)CC1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(CN4CCc5ccccc5C4)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-(chloromethyl)phenyl)[1,2,4]oxadiazol-3-ylmethyl]-1-(1-ethylpropyl)piperidine and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9]2([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>O>[CH3:20][N:19]([CH3:21])[C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
[8-(3-fluorophenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethylamine hydrochloride (7.2 g, 22.75 mmole) was dissolved in water (9.6 ml), conc. hydrochloric acid (14 ml, 455 mmole) was added and the mixture was stirred for 4 days at room temperature. After completion of the hydrolysis the reaction mixture was extracted with diethyl ether (2×50 ml), the aqueous phase was make alkaline with 5N sodium hydroxide solution while cooling with ice, whereupon the product precipitated out. The ketone Ket-7 was isolated as a yellow solid with a melting point of 83°-88° C. and in a yield of 50% (6.05 g).
Reaction SMILES: [NH2:1][C:2]([CH3:13])([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(N(CC)C(C)C)(C)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1.O>[CH2:39]([O:38][C:36]([NH:1][C:2]([CH3:13])([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: CC(N)(Cc1ccccc1)C(=O)O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a stirring suspension of D,L-Phe(αMe)-OH (7.5 g, 42 mmol) in tetrahydrofuran (250 mL) was added N,O-bis(trimethylsilyl)acetamide (12.8 g, 62.8 mmol). Upon clarification the solution was cooled to 0° C. and N,N-diisopropylethylamine (5.4 g, 42 mmol) was added, followed by ethyl chloroformate (4.5 g, 42 mmol). After 2 h, water (100 mL) was added and then the organic solvent was removed in vacuo. The aqueous phase was diluted with 1N NaOH and washed twice with diethyl ether. The aqueous phase was then acidified to pH 2 with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried (Na2SO4), filtered and concentrated in vacuo to give 10.3 g (98% yield) of a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C[Al](C)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]1[C:25]2[N:26]=[C:27]([NH:38][CH2:39][C:40](OC)=[O:41])[N:28]=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[C:24]=2[CH:23]=[CH:22][C:21]1=[O:44]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]1[C:25]2[N:26]=[C:27]([NH:38][CH2:39][C:40](=[O:41])[N:4]3[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]3)[N:28]=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[C:24]=2[CH:23]=[CH:22][C:21]1=[O:44]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C1CNCCN1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCNC(=O)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 29 %

Procedure:
Following the general procedure outlined in Example 193, piperazine-2-one (165 mg, 1.65 mmol), trimethylaluminum (0.83 mL, 1.65 mmol) and the product of Example 190 (150 mg, 0.33 mmol) were reacted to give the crude material. Preparative HPLC, eluting with acetonitrile/H2O (10/90, v/v to 90/10, v/v, over 10 min), followed by recrystallization from dichloromethane and hexane, gave the desired product 50 mg (29%). LC-MS: 523.2 (MH+, m/z), 1.68 (Rt, min).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:25])([F:24])C(OCC)=O)[CH:13]=2)=[CH:8][CH:7]=1)C.O>CO.[Li+].[OH-].CN(C=O)C.Cl>[F:25][CH:18]([F:24])[C:14]1[CH:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:26])=[O:3])=[CH:11][CH:10]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(C(F)(F)C(=O)OCC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Ethyl 2-(4-(4-(2-ethoxy-2-oxoethyl)phenyl)pyridin-2-yl)-2,2-difluoroacetate 203-4 (476 mg, 1.3 mmol) was dissolved in 5 mL MeOH and 2 mL 2N LiOH. The reaction mixture was stirred at 55° C. for 12 hrs. After cooling to room temperature, the mixture was redissolved in 5 mL DMF and 1.5 mL concentrated HCl. The solution was stirred at 130° C. for 3 hrs. After cooling to room temperature, the solution was poured into 5 ml water and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5. MS m/z 264.1 (M+1).
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=[CH:3]1.[CH:11]([N:14]=[C:15]=[S:16])([CH3:13])[CH3:12].Cl>C(#N)C.C(O)C>[ClH:1].[CH:11]([NH:14][C:15]([N:7]1[CH2:8][CH2:9][C:10]2[NH:2][CH:3]=[N:4][C:5]=2[CH2:6]1)=[S:16])([CH3:13])[CH3:12]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(C)N=C=S
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: CC(C)NC(=S)N1CCc2[nH]cnc2C1
Yield: 76.5 %

Procedure:
A solution of 2 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride and 2.5 g of isopropyl isothiocyanate in 20 ml of acetonitrile and 5 ml of ethanol is refluxed 8 h. Evaporation of the solvent leaves a residue that is treated with one equivalent of ethanolic hydrogen chloride. Evaporation of the solvent leaves a residue which is crystallized from acetone to give 2.5 g of 5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 170°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][C:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]2[N:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:35])[N:17]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
3.1 g 4-(2-(3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 20 mL dichlormethane and 20 mL trifluoracetic acid was added. The reaction was stirred for 24 h at RT and the solvent was evaporated. Potassium carbonate solution (10%) was added to the residue, the precipate was filtered and crystallized from a mixture of acetonitrile and isopropylether to yield 2.3 g of the desired compound. (M+H)+: 384
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1.[OH-:32].[Na+:33]>C1COCC1>[Na+:33].[Na+:33].[O:22]1[CH:23]=[CH:24][C:20]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:6]3[CH:25]=[C:2]([F:1])[CH:3]=[C:4]([C:26]([OH:31])([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:5]=3)=[CH:18][C:17]=2[OH:32])=[CH:14][C:15]([O-:16])=[O:19])=[CH:21]1.[O:22]1[CH:23]=[CH:24][C:20]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:6]3[CH:25]=[C:2]([F:1])[CH:3]=[C:4]([C:26]([OH:31])([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:5]=3)=[CH:18][C:17]=2[OH:32])=[CH:14][C:15]([O-:16])=[O:19])=[CH:21]1
Reactant: CCC(O)(CC)c1cc(F)cc(OCc2ccc3c(-c4ccoc4)cc(=O)oc3c2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cc(F)cc(OCc2ccc(C(=CC(=O)[O-])c3ccoc3)c(O)c2)c1
Reaction time: 16 h

Procedure:
A solution of the lactone from Step 1 in THF was treated with 2 equivalents of 1N NaOH and the mixture heated at reflux for 2 hrs. The solvent was removed in vacuo and the residue was lyophilized for 16 hrs to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:19]=[CH:18][CH:17]=1
Reactant: CCc1ccncc1C
Reactant: FC(F)(F)c1cccc(CCCBr)c1
Product: Cc1cnccc1C(C)CCCc1cccc(C(F)(F)F)c1
Yield: 47.4 %

Procedure:
1.83 g (15.1 mmol) of 3-methyl-4-ethylpyridine and 4.03 g (15.1 mmol) of 1-bromo-3-(3-trifluoromethylphenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.20 g of the desired compound (yield: 47.5%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C1C=CN=CC=1.O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C1CCNC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)N1CCCC1

Procedure:
17.5 g isatoic anhydride and 2.66 g 4-dimethylaminopyridine are combined in 500 ml tetrahydrofuran. 9.32 g of pyrrolidine is added and the mixture is heated at reflux overnight. The mixture is concentrated in vacuo, the residue taken into ethyl acetate and the organic solution washed with citric acid solution, water and brine and dried over magnesium sulfate. The solution is filtered, evaporated and the residue triturated in ether/hexane (1:5) to give N-(2-aminobenzoyl)pyrrolidine, m.p. 79°-81° C.