Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:31])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[C:40]1[N:44]2[CH:45]=[C:46]([O:49][C@H:50]3[C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[C@@H:53]([NH2:60])[CH2:52][CH2:51]3)[CH:47]=[CH:48][C:43]2=[N:42][N:41]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:60][C@@H:53]2[C:54]3[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:50]([O:49][C:46]3[CH:47]=[CH:48][C:43]4[N:44]([C:40]([C@@H:36]5[CH2:37][CH2:38][CH2:39][N:35]5[CH3:34])=[N:41][N:42]=4)[CH:45]=3)[CH2:51][CH2:52]2)=[O:31])[N:8]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c4)c4ccccc43)cn12
Yield: 107.6 %

Procedure:
A solution of Intermediate 62d (193 mg, 0.35 mmol) and Intermediate E (115 mg, 0.32 mmol) and DIPEA (166 μL, 0.94 mmol) in THF (3.5 mL) was stirred at reflux for 24 h. The cooled reaction mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo to give the title compound (265 mg, 99%). LCMS (Method 3): Rt 3.82 min, m/z 769 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-(-1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.5 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:24][C:21]2[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)C(CC2CCCC2)n2ncccc2=O)n1
Yield: 36 %

Procedure:
Using the method described in Example 78, Step 3, from 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (As prepared in Example 78, Step 2) and 1-methyl-1H-pyrazol-3-ylamine afforded 3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(6-oxo-6H-pyridazin-1-yl)-propionamide as a white solid (37.1 mg, 36%); ES+-HRMS m/e calcd for C16H21N5O2 [M+H+] 316.1768 found 316.1768. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.07 (br s, 1H), 1.24-1.36 (m, 1H), 1.36-1.49 (m, 2H), 1.49-1.74 (m, 5H), 1.93 (ddd, J=13.4, 8.6, 4.5 Hz, 1H), 2.18-2.31 (m, 1H), 3.73 (s, 3H), 5.51 (dd, J=10.7, 4.7 Hz, 1H), 6.35 (d, J=2.0 Hz, 1H), 6.94 (dd, J=9.5, 1.5 Hz, 1H), 7.42 (dd, J=9.5, 3.7 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.99 (dd, J=3.7, 1.5 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])=[N:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cn1)c1ccccc1[N+](=O)[O-]
Yield: 77.9 %

Procedure:
A solution of 2-nitrobenzoyl chloride (3.70 g, 20 mmol, 1.0 equiv), 2-amino-5-bromopyridine (3.50 g, 1.0 equiv), pyridine (10 mL) in 25 mL of methylene chloride was stirred overnight. The volatile was evaporated, flash chromatography on silica gel gave N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (5.02 g, 77%). MS found for C12H9BrN3O3 (M+H)+: 322.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:20]O>>[N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([O:12][CH3:20])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccnc(N2CCCCC2)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(N2CCCCC2)c1
Temperature: 0 °C

Procedure:
A mixture of 2-Piperidin-1-yl-isonicotinic acid (30 g, 0.145 mol) in methanol (500 mL) was cooled to 0° C. and then thionylchloride (42 mL) was added. The reaction mixture was refluxed for 20 h. The solvent was removed under vacuum and the residue was taken up in EtOAc (500 mL). The organic layer was washed with 10% aqueous NaHCO3 solution, water, brine and dried. The solvent was removed under vacuum to methyl 2-piperidin-1-ylisonicotinate (18 g, 56%) as yellow liquid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:24])[C:9]([C:22]#[N:23])=[CH:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]([OH:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:24])[C:9]([C:22]#[N:23])=[CH:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]([O:21][C:25](=[O:27])[CH3:26])=[CH:13][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(=Cc1ccc(O)c2c1CCCC2)C(=O)Nc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C(C#N)C(=O)Nc2ccccc2)c2c1CCCC2
Yield: 80 %

Procedure:
To a cooled solution of N-phenyl β-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)-α-cyanoacrylamide (3.184 g, 0.010 mol) in dry pyridine (5 ml) was added acetic anhydride (2.040 g, 0.020 mol) and the mixture maintained at 0°-5° C. overnight. Thereupon the mixture was concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product was crystallized from chloroform/methanol to yield pure title compound in about 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[N:8](COC(=O)[C@@H](C3C=CC=CC=3)O)[C:7]=2[CH:36]=1.[OH-].[Na+].C(OC)=O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:36]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(COC(=O)[C@H](O)c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC=O
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 77 %

Procedure:
0.23 g (0.45 mmol) of the more hydrophilic diastereomer of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[(R)-mandeloyloxymethyl]-1H-benzimidazole was dissolved in 15 ml methanol. A solution of 36 mg (0.9 mmol) sodium hydroxide in 0.45 ml water was added, and after 10 minutes the mixture was evaporated on a rotavapor. The residue was partitioned between 15 ml water and 15 ml dichloromethane. The organic solution was extracted with 15 ml water and to the combined aqueous solutions was added 85 μL (1.4 mmol) methyl formate. After 15 minutes the mixture was extracted with 3×10 ml dichloromethane. The organic solution was dried over Na2SO4 and then evaporated. There was obtained 0.12 g (77%) of the title compound as a colorless syrup. The optical purity (e.e.) which was analyzed by chiral column chromatography was 94%. [α]D20=−155° (c=0.5%, chloroform).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Reactant: O=C(Cl)c1cccnc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)c2cccnc2)cc1

Procedure:
Following a procedure similar to that described above in Example 30A, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with nicotinoyl chloride, there is obtained 3-(nicotinoyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3- nicotinoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl) benzyl alcohol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (9.2 mg) with purity >90%: MS (pos) m/z 459.2, 461.2, 463.2.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51]>C(OCC)(=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51])=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCCCOC(=O)COCCCN
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)COCCCNC(=O)c1sc(NC(=N)N)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
175 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 2.6 ml of DMF, 0.29 ml of N-MM and 332 mg of HBTU are stirred at room temperature (RT) for one hour, treated with 197 mg of butyl (3-amino-propoxy)-acetate hydrochloride and stirred at RT for a further 18 hrs. For the working up, the mixture is diluted with ethyl acetate, washed with dilute sodium carbonate solution, dilute sodium chloride solution and saturated sodium chloride solution, dried and evaporated in a vacuum. Chromatography on silica gel with methylene chloride-alcohol gives 162 mg of butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy}-acetate, mass spectroscopy (MS): 372 (M+H)+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)C.[OH-].[Na+]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12](=[O:11])[CH2:2][C:1]#[N:3])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(OCC)cc1
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.5 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 11 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 4-ethoxy-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(4-ethoxy-phenyl)-3-oxo-propionitrile in the amount of 2.5463 gms.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][N:7]=1)[CH3:2].B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:48]([O:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:49].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:51]([O:50][C:48]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[CH2:1][CH3:2])[CH:10]=1)(=[O:26])=[O:25])=[O:49])[CH2:52][CH2:53][CH3:54]
Reactant: CCc1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2CC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 3-[3-(2-ethylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (55.1 mg, 0.120 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous MgSO4, concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (35.5 mg, 0.240 mmol) and butyl chloroformate (152.5 μL, 1.20 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95 to 8:92) as eluent to give the title compound in 73% yield, over two steps, (44.3 mg, 0.088 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21][CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:46])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Example 112 (2.7 g) in methylene chloride (50 ml) was added m-chloroperbenzoic acid (70%, 1.2 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and then water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain tert-butyl (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)-acetate from the fraction eluted with ethyl acetate. It was recrystallized from ethyl acetate-hexane (2.2 g, 79%). Colorless prisms. Melting point 175–176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH:31]1[CH2:34][NH:33][CH2:32]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC>[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH:31]1[CH2:34][N:33]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:32]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NC1CNC1)OCc1ccccc1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Solvent: CCOCC
Product: COc1ccc2nccc(N3CC(NC(=O)OCc4ccccc4)C3)c2n1

Procedure:
According to procedure F and starting from trifluoromethanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (prepared according to WO 02/008224) and azetidin-3-yl-carbamic acid benzyl ester the desired intermediate was isolated after trituration with ether as a colorless solid (5.05 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:14][O:13][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:10][CH3:15])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C)c(OC)c(OC)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(OC)c(OC)c1OC
Yield: 97.6 %

Procedure:
According to a modification of the procedure by Brimble et al.,36 11 (0.660 g, 3.33 mmol) and K2CO3 (4.08 g, 29.5 mmol) were added to a flame-dried 250 mL round bottom flask followed by dry acetone (120.0 mL) and MeI (2.0 mL, 32 mmol) at room temperature. A water-jacketed reflux condenser was attached and the reaction was heated under reflux for 12 hours. The reaction was then cooled, filtered, and the solvent was removed under reduced pressure. The brown residue was then resuspended in CH2Cl2, dried over MgSO4, filtered, and condensed. The resulting colorless oil was then purified by flash chromatography (1:9 EtOAc:hexanes) to provide 6 (0.690 g, 3.25 mmol, 99%) as a colorless oil.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([CH3:31])=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=4)[N:19]=[C:13]3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.C(O)C.N>>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([CH3:31])=[C:18]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](=[NH:29])[NH2:30])=[CH:26][CH:27]=4)[N:19]=[C:13]3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccn12
Yield: 92 %

Procedure:
Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 92% of theory, C27H27N5O3 (469.55) Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU119##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClC(Cl)C.ClCCl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:10][C@H:9]3[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
A suspension of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.30 g, 1.69 mmol) and 4-(2-pyridinyl)benzaldehyde (0.37 g, 2.03 mmol) in dichloroethane (10 mL) were heated to reflux until a clear solution formed. The solution was cooled to RT then NaB(OAc)3H (0.54 g, 2.54 mmol) was added and stirred for 2 h. Water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from 20% ethyl acetate/hexanes to 100% ethyl acetate to give the title compound as a white solid (0.13 g, 22%). 1H NMR (400 MHz, DMSO) δ 12.15 (s, 1H), 8.65 (d, J=4.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.92 (d, J=8.2 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.32 (dd, J=5.2, 6.6 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.50 (d, J=8.4 Hz, 2H), 6.23 (s, 1H), 4.30 (d, J=4.6 Hz, 2H), 2.22-2.17 (m, 1H), 1.61-1.57 (m, 1H), 1.31-1.27 (m, 1H), 1.20-1.16 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>CC#N.O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(N)cn1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC)nc2)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 4.4 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (58 mg, 0.20 mmol) and 6-methoxypyridin-3-amine (49 mg, 0.40 mmol) was dissolved in MeCN (11.0 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 5 mins. The reaction mixture was diluted with MeCN and water and purified by preparative HPLC using MeCN/0.1M NH4OAc as eluant giving the title compound (3.4 mg, 4.3%). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, 1H), 7.25-7.1 (m, 4H), 7.0 (bs, 1H), 6.85 (dd, 1H), 6.3 (d, 1H), 3.78 (t, 2H), 1.9-1.8 (m, 2H), 1.5-1.4 (m, 2H), 1.0 (t, 3H); Mass Spectrum: M−H+ 386.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Br:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].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>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Br:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccc(Br)cc2C1
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: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (250 mg, 1.21 mmol), 2-amino-5-bromo-indan-2-carboxylic acid ethyl ester (344 mg, 1.21 mmol), HATU (551 mg, 1.45 mmol) in anhydrous DMF (10 mL) is added DIPEA (240 μL, 1.45 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-70% EtOAc in heptane) to give a pure product (100) as a colorless oil (520 mg, 91%).