Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:13]3([CH2:15][CH:14]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=S)[NH:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1.[C:28]([NH:31][NH2:32])(=O)[CH3:29]>CCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:13]3([CH2:15][CH:14]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]3=[N:32][N:31]=[C:28]([CH3:29])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1NC2=S
Solvent: CCCCO
Product: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1-n1c(C)nnc12
Yield: 41.7 %

Procedure:
A solution of ethyl 1-(4-chlorophenyl)-2-oxo-4-thioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (70 mg, 0.17 mmol) and acetohydrazide (60 mg, 0.78 mmol) in n-BuOH (20 mL) was heated at 130° C. overnight. The solution was evaporated and purified by CombiFlash (DCM:MeOH=10:1) to afford ethyl 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylate (30 mg, 41%). LRMS (M+H)+: 422 m/z. 1H NMR (300 MHz, CD3OD): δ 1.04-1.08 (t, J=7.2 Hz, 3H), 1.92-1.97 (m, 1H), 2.10-2.18 (m, 2H), 2.74 (s, 3H), 3.87-4.03 (m, 2H), 6.96-6.99 (m, 1H), 7.23-7.27 (m, 2H), 7.41-7.54 (m, 4H), 7.69-7.72 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1.C(Cl)Cl.[CH:18]([C@@:21]1([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:25][C@H:24]([NH2:26])[CH:23]=[CH:22]1)([CH3:20])[CH3:19].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]([C@@:21]1([C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=3)[CH2:33][CH2:34]2)=[O:28])[CH2:25][C@H:24]([NH:26][CH:8]2[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH:3]2[O:2][CH3:1])[CH:23]=[CH:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)C=C[C@@H](N)C1
Reactant: CCOC(=O)N1CCC(=O)C(OC)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(N[C@@H]2C=C[C@@](C(=O)N3CCN(c4cc(C(F)(F)F)ccn4)CC3)(C(C)C)C2)C(OC)C1
Reaction time: 8 h

Procedure:
The title compound was prepared by taking ethyl 3-methoxy-4-oxopiperidine-1-carboxylate (148 mg, 0.000737 mol) in Methylene chloride (3 mL, 0.04 mol) and adding (1S,4S)-4-isopropyl-4-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopent-2-en-1-amine (0.31 g, 0.00081 mol;), Triethylamine (0.8 mL, 0.006 mol;) and Sodium triacetoxyborohydride (0.312 g, 0.00147 mol). The reaction was stirred overnight. The reaction was quenched with (20 mL) NaOH and extracted with (3×10 mL) CH2Cl2. The organic layers were collected, dried over MgSO4 and concentrated in vacuo. The crude was taken on to the next step as-is (410 mg, 98%). MS calculated for C28H40F3N5O4: (M+H) 568; found 568.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:18])([F:19])/[CH:16]=[CH:17]/[C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(I)cc1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-fluoro-4-iodo-benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH:25]([C:34]#[N:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C.CCOCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[NH:24][C:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[C:34]([Cl:37])[N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NC(C#N)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)OCCn2c1nc(-c1nc(Cl)c(Cc3ccc(F)cc3)[nH]1)c(OCc1ccccc1)c2=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
(procedure adapted from Org. Lett. 2004, 6, 629-631). To a solution of 3-(benzyloxy)-N-(1-cyano-2-(4-fluorophenyl)ethyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.48 g, 1.01 mmol, 1.0 equiv) and CCl4 (0.24 mL, 2.52 mmol, 2.5 equiv) in acetonitrile (10 mL) under a nitrogen atmosphere, was added PPh3 (0.39 g, 2.52 mmol, 2.5 equiv). The reaction was heated to 45° C. (oil bath). After stirring 18 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was treated with CH2Cl2 (10 mL) and 0.5 M NaOH (20 mL) and stirred vigorously. After stirring 4 h, the mixture was poured into water and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-80% ethyl acetate/hexane) to provide a viscous yellow oil. This oil was taken up in ether and seeded with a crystal of previously isolated material. After crystallization, the solid was filtered to provide the title compound (0.32 g, 64% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 7.28-7.41 (m, 5H), 6.91-6.96 (m, 4H), 5.27 (s, 2H), 3.95-4.11 (m, 4H), 3.77 (s, 2H), 1.67 (s, 6H); LCMS (ES+, (M+H)+) m/z 495.14.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH3:60])(O)[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(B(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.C([SiH3])CCC.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([CH3:60])[CH2:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: CCCC[SiH3]
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
To a solution of 45 (38 mg, 46 μmol) in dry DCM (1 mL) flushed with argon was added tris(pentafluorophenyl)borane (5 mg, 9.6 μmol). After stirring for 10 min, n-butylsilane (8 μL, ˜2 equiv) was added. Stirring was continued for 3 days. The mixture was directly loaded onto a preparatory TLC plate, developed with 15% EtOAc in petroleum ether to give 46 (21 mg, 56% yield) as a single diastereomer. 1H NMR (300 MHz, CDCl3) δ 7.14-7.31 (m, 19H), 6.81-6.99 (m, 6H), 4.86 (d, J=10.5 Hz, 1H), 4.81 (s, 2H), 4.58 (d, J=12.0 Hz, 2H), 4.45 (d, J=12.0 Hz, 1H), 4.33 (d, J=10.8 Hz, 1H), 4.07-4.16 (m, 2H), 4.04 (d, J=15.0 Hz, 1H), 3.61-3.89 (m, 8H), 2.49 (q, J=7.5 Hz, 2H), 2.15-2.20 (m, 2H), 1.41 (d, J=6.0 Hz), 1.11 (t, J=7.5 Hz, 3H).LCMS m/z 832 (M+Na), 810 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH:29]4[O:34][C:33]5[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=5[O:31][CH2:30]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl- 1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol- 3-yl)-1-piperidinyl]methyl-1,4benzodioxan as off-white crystals, 2.22 g, m.p.=8687° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+]([O-])=O)[CH:3]=1.[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>CCO>[N+:12]([O-:15])([OH:14])=[O:13].[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17]([NH2:18])=[NH:16])=[C:3]([N+:12]([O-:15])=[O:13])[CH:4]=1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc(O)cc1[N+](=O)[O-]
Yield: 54 %

Procedure:
A mixture of 4-amino-2-nitrophenol (25 mmol, 3.85 g) in EtOH (6 mL) on an ice bath was treated with nitric acid (69% aq soln.; 1.8 mL). To this of cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 22 h. The solvent was evaporated. The dark brown solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a grey solid (3.53 g, 54%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)=[CH:11][CH:12]=1.[OH-].[Li+]>CO.O1CCCC1>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (+/−)-ethyl 4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoate (46 mg, 0.095 mmol) in methanol (0.19 ml) and tetrahydrofuran (0.095 ml) was treated with aqueous lithium hydroxide (0.095 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. The mixture was then concentrated in vacuo a second time, and the crude residue was used directly for further transformations.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]=3[CH:29]=2)=[CH:8][CH:7]=1>CO.Cl.O1CCOCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:29]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1c[nH]c(-c2ccc(-c3ccc4c(c3)CNCCO4)cn2)n1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxylate (50 mg, 0.13 mmol) in a mixture of methanol (2 mL) and 4N hydrochloric acid in dioxane (2 mL) was refluxed for 5 min. After cooling to room temperature and the reaction mixture was concentrated. The residue was then concentrated from chloroform (3×) and dried to give crude 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH2:25][CH3:26])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1NCCc2ccc(F)cc21
Product: CCC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C[Si](C)(C)Cl.[CH3:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(OC(C)C)(=O)C.[Zn]>[OH:11][C:7]([CH3:6])([CH2:8][CH2:9][CH3:10])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCC(C)=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: CCCC(C)(O)CC(=O)OCC
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 11.2 g of zinc powder (170 mmol) in 65 ml of isopropyl acetate. After 3.2 ml of trimethylchlorosilane (25 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 60° C., following which 9.7 g of neat pentan-2-one (113 mmol) were added and then, over the course of 8 min, 22.6 g of neat ethyl bromoacetate (136 mmol) were added dropwise, the temperature being maintained at 60° C. by external cooling. The mixture was then stirred for 25 min at 60° C., and following cooling to 0° C., was acidified with 65 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration, and the organic phase separated. The organic phase was stirred at 0° C. with 60 ml of 1 N hydrochloric acid and then washed with 30 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. The isopropyl acetate solvent was recovered to an extent of greater than 90%). Distillation gave ethyl 3-hydroxy-3-methylcaproate in a yield of 18.2 g (93% of theory) with a boiling point of 41° C. (0.31 mbar).
Reaction SMILES: [CH2:1]([CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH2:1]([CH:8]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:9]([O:11][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)c1c[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
To a solution of α-benzylindole-3-acetic acid (12 g) in methanol (200 mL), was added 2 mL of concentrated H2SO4 ; the mixture was stirred at reflux temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to a volume of about 50 mL, then diluted with 200 mL of toluene. The toluene solution was washed with water, saturated NaHCO3 solution, and again with water. On evaporation, if afforded 12.3 g (97.6% crude yield) of product as a light brown viscous oil. The crude product slowly crytallized on standing at room temperature. It was triturated with heptane to give fine white crystals, m.p. 62°-68° C.
Reaction SMILES: C([N:8]([C:20](=[O:54])[CH2:21][CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([P:42]([CH2:46][CH3:47])([CH2:44][CH3:45])=[O:43])[P:36]([CH2:40][CH3:41])([CH2:38][CH3:39])=[O:37])[C:26]([CH3:48])=[CH:25][C:24]=1[O:49][C:50](=[O:53])[CH2:51][CH3:52])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:50]([O:49][C:24]1[CH:25]=[C:26]([CH3:48])[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([P:36]([CH2:38][CH3:39])([CH2:40][CH3:41])=[O:37])[P:42]([CH2:44][CH3:45])([CH2:46][CH3:47])=[O:43])=[C:28]([CH3:29])[C:23]=1[CH2:22][CH2:21][C:20]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:54])(=[O:53])[CH2:51][CH3:52]
Reactant: CCC(=O)Oc1cc(C)c(OCCCCC(P(=O)(CC)CC)P(=O)(CC)CC)c(C)c1CCC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Oc1cc(C)c(OCCCCC(P(=O)(CC)CC)P(=O)(CC)CC)c(C)c1CCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
Compound 135 (272 mg, 0.335 mmol) was treated with a 50% v/v solution of TFA in CH2Cl2 (4 mL). After stirring for 3 hr the reaction mixture was concentrated to dryness and coevaporated with toluene. After drying under vacuum, acid 136 was obtained as a colorless liquid (304 mg, 120%) and was used without purification. 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.3, 3H), 1.32-1.37 (m, 12H), 1.70-1.81 (m, 4H), 1.93-2.02 (m, 2H), 2.13 (s, 3H), 2.20 (s, 3H), 2.20-2.29 (m, 2H), 2.47 (tt, J=5.8, 24.5, 1H), 2.57 (q, J=7.7, 2H), 2.74-2.81 (m, 1H), 2.87-2.93 (m, 1H), 3.01 (dd, J=6.2, 14.0, 1H), 3.15 (dd, J=5.5, 14.0, 1H), 3.66 (t, J=6.8, 2H), 4.14-4.22 (m, 8H), 4.75-4.80 (m, 1H), 6.12 (d, J=7.6, 1H), 6.67 (s, 1H), 7.06-7.09 (m, 2H), 7.14-7.24 (m, 3H): 31P (162 MHz, CDCl3) δ 24.35 (s, 1 P), 24.39 (s, 1 P).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=[S:42])[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=S(=O)(c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1)N1CCC1
Yield: 37.1 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 258 mg of 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B6) and 242 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-5 vol. % ethanol) affords 99 mg of the title compound as a beige foam. ESI-MS: 470.2 (MH+). TLC: Rf=0.45 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Cl:20][C:21]1[C:22]([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Cl:20][C:21]1[C:22]([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[N:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: O=C(O)Cn1c(=O)ccc2nc(C(F)(F)F)ccc21
Product: O=C(Cn1c(=O)ccc2nc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (160 mg, 0.588 mmol) and 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (59 mg, 0.294) mmol) according to protocol A. Retention time (min)=5.046, method [7], MS(ESI) 455.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.30 (d, J=8.9 Hz, 1H), 8.21 (d, J=9.8 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.20 (s, 1H), 7.13 (d, J=9.8 Hz, 1H), 5.36 (s, 2H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]1[CH2:10]O[CH2:8][CH2:7]1>>[CH3:1][Si:2]([CH3:4])([CH3:8])[C:3]1[CH:7]=[C:6]([CH3:10])[C:8]([Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:7][C:6]=1[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: C1CCOC1
Product: Cc1cc([Si](C)(C)C)c(C)cc1[Si](C)(C)C
Yield: 61 %

Procedure:
10.52 g of 2,5-dibromo-p-xylene (40 mmol) was reacted with 2.08 of magnesium turnings (88 mmol) in 40 ml of anhydrous THF for 4 hours with refluxing (initiated by iodine) to give the 2,5-bisbromomagnesium-p-xylene Grignard reagent. To this solution, cooled in an ice bath, was added a solution of 11.2 ml trimethylsilyl chloride (88 mmol) in 40 ml of anhydrous THF. The mixture was refluxed for 24 hours and then cooled in an ice bath. After it was quenched with saturated ammonium chloride aqueous solution, THF was evaporated and the residue was extracted with hexane (30 ml×2). The combined organic layers were washed with water, brine and then dried over anhydrous magnesium sulfate. After the solution was evaporated under a reduced pressure, the residue was recrystallized in ethanol to afford white plate crystals 6.1 g, (yield 61%). M.p. 56.0-57.5° C. MS: 250. 1H NMR (300 MHz, CDCl3, ppm) δ 0.31 (18H, s, —Si(CH3)3), 2.42 (6H, s), 7.24 (2H, s). Anal. Calcd for C14H26Si2: C, 67.12; H, 10.46. Found: C, 66.94; H, 10.23.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]([F:38])[C:30]2[O:34][C:33](SC)=[N:32][C:31]=2[CH:37]=1>C([O-])(=O)C.C([O-])(=O)C.[Hg+2]>[Br:26][C:27]1[CH:28]=[C:29]([F:38])[C:30]2[O:34][C:33]([NH:15][C@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:24][CH:23]=3)=[N:32][C:31]=2[CH:37]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: CSc1nc2cc(Br)cc(F)c2o1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3cc(Br)cc(F)c3o2)C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
The mixture constituted by aminoester 4-2 (865 mg; 2.46 mmoles), 5-bromo-7-fluoro-2-(methylthio)-benzoxazole (804 mg; 3.07 mmoles) and mercury diacetate (437 mg) is agitated for 3 hours, under nitrogen and at 100° C. After cooling down, the medium is chromatographed eluting with a CH2Cl2/ethyl acetate mixture 95/5, 564 mg of expected product is obtained, which is repurified by recrystallizing from isopropyl oxide. 528 mg of purified product is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C1O[C:11]2([C:20]3[C:14]4[C:15](=[CH:21][N:22]([S:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)(=[O:26])=[O:25])[CH2:23][C:13]=4[CH2:12]2)[CH:16]=[CH:17][O:18][CH:19]=3)[O:10]C1>O>[C:27]1([S:24]([N:22]2[CH2:23][C:13]3[CH2:12][C:11](=[O:10])[C:20]4=[CH:19][O:18][CH:17]=[CH:16][C:15]([C:14]=34)=[CH:21]2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(c1ccccc1)N1C=C2C=COC=C3C2=C(C1)CC31OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CC2=C3C(=CN(S(=O)(=O)c4ccccc4)C2)C=COC=C13
Temperature: 80 °C
Yield: 78 %

Procedure:
Trifluoroacetic acid 1 ml and water 0.1 ml were added to compound (34) 48.4 mg. The mixture was heated at 80° C. for 15 min and concentrated under reduced pressure. Ice-water was added to the residue, which was made alkaline with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:2) to give the titled compound (35) as a colorless oil, 33.2 mg. Yield 78%.