Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:18]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To 100 ml. of 1,2-dichloroethane were added 5.0 g. (0.021 mole) of 3-phenyl-6-methoxybenzothiophene and 2.81 g. (0.021 mole) of benzoyl chloride. The mixture was cooled to 0° C., and 2.93 g. (0.022 mole) of aluminum chloride were added. The mixture was stirred for one hour, and ice then was added. The resulting organic layer was separated, washed with water, and evaporated. To the residue were added 250 ml. of methanol and 10 ml. of 5N sodium hydroxide. The mixture was refluxed for 30 minutes, evaporated, and ether and water were added to the residue. The ether layer was separated, washed with 1N sodium hydroxide, 1N hydrochloric acid, and aqueous soidum chloride. The ether layer then was dried over magnesium sulfate, filtered, and evaporated. The residue was crystallized from methanol to obtain 3.77 g. (52 percent) of the title compound, m.p. 94°-95.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]=1[S:14][C:13]1[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=1)[N:7]=2.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[OH:20]
Reactant: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2
Yield: 79.5 %

Procedure:
The compound from Step 4 (300 mg) was suspended in ethyl acetate (100 ml) and a solution of Na2S2O4 (2 g) in water (40 ml) was then added and the mixture was shaken until the orange-red coloration disappeared. The aqueous layer was decanted, the organic layer was washed with water, dried and evaporated to dryness. The resulting residue was treated with ether and filtered to afford the title compound (240 mg), m.p. 185° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][C:22]#[N:23].CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([CH2:21][O:11][C:10](=[O:12])[C@@H:9]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)#[N:23]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Compound 93d (0.494 g, 1.324 mmol) was dissolved in DMF (10 ml), and 2-bromoacetonitrile (0.63 g, 5.30 mmol) and DIPEA (0.341 g, 2.65 mmol) were slowly added at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to afford (S)-3-(3-iodo-phenyl)-2-pent-4-enoylamino-propionic acid cyanomethyl ester (Compound 93e) (0.392 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:33])[N:7]([CH3:8])[CH:9]([CH3:32])[C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1ccc(Br)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C(=O)Nc1ccc(-c2cncnc2)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]-N-methylcarbamate C1a (3.5 g, 6.5 mmol), pyrimidin-5-ylboronic acid (1.0 g, 7.8 mmol), Na2CO3 (1.4 g, 13.2 mmol), Dichlorobis(triphenylphosphine)palladium(II) (450 mg, 0.64 mmol), dioxane (20 ml), MeOH (5 ml) and water (3.5 ml) is stirred under argon atmosphere for 17 h at 80° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 2.33 g (67%). HPLC-MS: M+H=538; tR=2.26 min (*Method—4).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][CH2:10][C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Nc1ccccc1F
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccccc1F
Yield: 11.4 %

Procedure:
To a solution of 2-fluoroaniline (22.06 g, 0.198 mol) and freshly distilled tert-butyl acrylate (25.145 g, 0.198 mol) in dry benzene (250 ml) was added tin tetrachloride (1 ml) and the mixture was refluxed for 60 h. The resulting suspension was filtered and the filtrate was evaporated to give a semisolid which was chromatographed on silica gel eluting with 25/75 ethyl acetate/hexane to give the title compound (5.4 g, 11%). Anal calcd for C13H18NO2F: C, 65.25; H, 7.58; N, 5.85. Found: C, 65.49; H, 7.75; N, 5.80. MS M+1 calcd for C13H18NO2F 240, found 240.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cnc2cccc(Cl)c21
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2cccc(Cl)c21)c1ccc(C(C)(C)C#N)c(F)c1

Procedure:
The amide is synthesized according to example 1 by mixing (7-chloro-1H-benzimidazol-1-yl)acetic acid (521 mg, 2.48 mmol) prepared according to scheme 1, 2-[4-(1-Aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride 721 mg, 2.97 mmol) prepared according to scheme 7, Et3N (824 μL, 5.95 mmol) and HATU (1.13 g, 2.97 mmol) in DMF (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5 u) 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA), (421 mg as TFA salt, 0.82 mmol, 33%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=7.03 Hz, 3H), 1.64-1.76 (m, 6H), 4.88-4.98 (m, 1H), 5.27 (s, 2H), 7.18-7.28 (m, 3H), 7.28-7.33 (m, 1H), 7.41 (t, J=8.30 Hz, 1H), 7.65 (d, J=7.81 Hz, 1H), 8.47 (s, 1H), 8.85 (d, J=7.62 Hz, 1H). MS [M+H], calcd: 399.9, found: 399.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C:8]2[S:7][CH:6]=[N:5][C:4]=2[CH2:3]1.C([Li:14])(C)(C)C.[C:15](=[O:17])=[O:16]>O1CCCC1>[CH3:1][N:2]1[CH2:9][C:8]2[S:7][C:6]([C:15]([O-:17])=[O:16])=[N:5][C:4]=2[CH2:3]1.[Li+:14]
Reactant: [Li]C(C)(C)C
Reactant: O=C=O
Reactant: CN1Cc2ncsc2C1
Solvent: C1CCOC1
Product: CN1Cc2nc(C(=O)[O-])sc2C1
Product: [Li+]
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (155 mg) was dissolved in tetrahydrofuran (7 ml) in an argon atmosphere, and the solution was cooled to −78° C., to which tert-butyllithium (1.54N pentane solution, 0.792 ml) was added dropwise. The reaction mixture was stirred for 1 hour under ice cooling and cooled again to −78° C. After blowing carbon dioxide into the reaction mixture for 20 minutes, it was heated to room temperature. The reaction mixture was concentrated under reduced pressure to obtain crude lithium 5-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-2-carboxylate. This product was dissolved in N,N-dimethylformamide (20 ml), and to this solution, were added (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (364 mg), 1-hydroxybenzotriazole monohydrate (150 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (426 mg). After the resultant mixture was stirred overnight, the solution was concentrated, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (methanol:dichloromethane=7:93). A 1N ethanol solution of hydrochloric acid and ethyl acetate were added to the thus-obtained product, and powder deposited was collected by filtration to obtain the title compound (343 mg) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:43][CH2:42][C:31]3[N:32]=[CH:33][N:34]=[C:35]([O:36][C@H:37]4[CH2:41][CH2:40][NH:39][CH2:38]4)[C:30]=3[CH2:29]2)=[CH:24][C:23]=1[CH3:44]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:8]([N:39]2[CH2:40][CH2:41][C@H:37]([O:36][C:35]3[C:30]4[CH2:29][N:28]([C:25]5[CH:26]=[N:27][C:22]([O:21][CH3:20])=[C:23]([CH3:44])[CH:24]=5)[CH2:43][CH2:42][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38]2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5oc(C)nc5C)C4)c3C2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of 2,4-dimethyl-oxazole-5-carboxylic acid (36.4 mg, 0.258 mmol), HTBU (98 mg, 0.258 mmol), DIPEA (86p1, 0.49 mmol) in DMF (5 mL) was stirred at rt for 20 min. then a solution of 6-(6-methoxy-5-methyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared in example 1, method 1b, step 2) (80 mg, 0.23 mmol) and DIPEA (86 μl, 0.49 mmol) in DMF (0.4 mL) was added. The reaction mixture was stirred 30 min at rt. The reaction mixture was directly purified by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-HCO3 MP gave (2,4-dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone (91 mg, 84% yield) as a white lyophilized powder. 1H-NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.27-2.52 (m, 8H) 2.95-3.03 (m, 2H) 3.44-3.55 (m, 2H) 3.70-4.26 (m, 9H) 5.76-5.92 (m, 1H) 7.40 (br. s., 1H) 7.64 (br. s., 1H) 8.55-8.62 (m, 1H), LCMS: [M+H]+=465.2, Rt(1)=1.51 min.
Reaction SMILES: C([N:5]=C=[O:7])(C)(C)C.O.[NH2:9][C:10]1[C:11]([C:18]([N:20]=[CH:21][NH:22]NC(NC(C)(C)C)=O)=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1.[NH2:31][C:32]1[C:33]([C:40]([N:42]=[CH:43][NH:44][NH:45][C:46]([NH:48]C(C)(C)C)=[O:47])=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1>>[OH2:7].[ClH:17].[NH2:31][C:32]1[C:33]([C:40]([N:42]=[C:43]([NH:44][C:18]([NH2:20])=[O:19])[NH2:5])=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1.[NH2:9][C:10]1[C:11]([C:18]([N:20]=[C:21]([NH2:22])[NH:45][C:46]([NH2:48])=[O:47])=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1.[ClH:17]
Reactant: CC(C)(C)NC(=O)NNC=NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)N=C=O
Solvent: O
Product: Cl
Product: NC(=O)NC(N)=NC(=O)c1nc(Cl)c(N)nc1N

Procedure:
Following the procedure of Example 23, Steps A and B but using the following pyrazinecarboxamides in place of the pyrazinecarboxamide used in Example 23, Step A, but using an equivalent amount of t-butylisocyanate and then following the procedure of Example 23B but using the appropriate pyrazinecarboxamide from Step A of that example the appropriate end product as listed is obtained.
Reaction SMILES: B.[Br:2][C:3]1[C:28]([F:29])=[CH:27][C:6]2[O:7][C:8]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:9]=3[C@H:10]3[C@H:15]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:14][CH2:13][C:12](=O)[N:11]3[C:5]=2[CH:4]=1.O>C1COCC1.C(OCC)(=O)C>[Br:2][C:3]1[C:28]([F:29])=[CH:27][C:6]2[O:7][C:8]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:9]=3[C@H:10]3[C@H:15]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: COC(=O)N[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Temperature: 30 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Borane (1.0 M in THF, 38.3 mL, 38.3 mmol) was added dropwise to a stirred solution of methyl (±)-(cis)-(7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamate (38.2 mmol) in THF (200 mL). The resulting mixture was stirred at 30° C. for 1 h. Subsequently, water was added dropwise until evolution of gas ceased. The resulting mixture was stirred for 1 h and then diluted with ethyl acetate (300 mL) and washed with brine. After drying (Na2SO4) the solvent was evaporated under reduced pressure to yield the crude title compound (16.7 g, 100%). (m/z)=439+441 (M+H)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:15][O:16][S:17]([F:20])(=[O:19])=[O:18]>>[F:20][S:17]([O-:19])(=[O:18])=[O:16].[CH3:15][N+:11]1[S:12][CH:13]=[CH:14][C:10]=1[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccsn1
Reactant: COS(=O)(=O)F
Product: CCCCCCCCOc1ccs[n+]1C
Product: O=S(=O)([O-])F

Procedure:
3-n-Octoxyisothiazole (5.0 g, 0.023 mol) and 6 ml of methylfluorosulfonate were heated to 70° for 1 hr. After cooling, the solid was washed with ether to yield 6.4 g of 2-methyl-3-n-octyloxyisothiazolium fluorosulfonate, mp 39°-41°. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:52][CH2:51][C:50]([CH3:54])([CH3:53])[CH2:49][C:48]=5[C:55]5[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=5)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH:62]1([NH:65][CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:63]1.C(O)(=O)C.C([BH3-])#N>O1CCCC1>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:48]2[CH2:49][C:50]([CH3:53])([CH3:54])[CH2:51][CH2:52][C:47]=2[CH2:46][N:43]2[CH2:44][CH2:45][N:40]([C:38]3[CH:37]=[CH:36][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][CH:29]([N:65]([CH2:66][CH2:67][C:68]#[N:69])[CH:62]6[CH2:64][CH2:63]6)[CH2:28][CH2:27]5)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:39]=3)[CH2:41][CH2:42]2)=[CH:56][CH:57]=1
Reactant: N#CCCNC1CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC(=O)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC(N(CCC#N)C6CC6)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 340C (240 mg) and 3-(cyclopropylamino)propanenitrile (62 mg) in tetrahydrofuran (10 mL) was added acetic acid (2 mL) and MP-cyanoborohydride (300 mg, 2.15 mmol/g). The mixture was stirred overnight. The mixture was filtered and concentrated under vacuum and the residue was dissolved in dimethylsulfoxide/methanol (1:1, 10 mL) and loaded on Gilson, C18 (100A) 250×121.2 mm (10 micron), with 30% acetonitrile to 65% acetonitrile over 40 minutes. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.66 (s, 1 H), 8.55 (dd, 1 H), 8.17 (d, 1 H), 8.03 (d, 1 H), 7.79 (d, 1 H), 7.49 (m, 3 H), 7.34 (d, 2 H), 7.11 (m, 1 H), 7.04 (d, 2 H), 6.67 (dd, 1 H), 6.38 (d, 1 H), 6.19 (d, 1 H), 4.01 (m, 1 H), 3.56 (m, 1 H), 3.06 (m, 4 H), 2.88 (t, 2 H), 2.65 (m, 6 H), 2.19 (m, 6 H), 2.00 (m, 7 H), 1.51 (m, 6 H), 0.92 (s, 6 H), 0.42 (m, 4 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10](=O)([O-])[O-].[K+].[K+].BrC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[CH2:10][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: BrCc1cccc2ccccc12
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (2.44 g; 20 mmol) in DMF (50 ml) were added potassium carbonate (3.04 g; 22 mmol) and bromomethylnaphthalene (4.64 g; 21 mmol), and the resulting mixture was stirred at room temperature for 16 h. The mixture was then poured into water (200 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel; methylene chloride-ethyl acetate 19:1) to provide 5.1 g of 3-(2-naphthylmethoxy)benzaldehyde.
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[C@H:10]([CH3:13])[C@H:9]1[C:14]([OH:16])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:18][CH:19]([N-]C(C)C)C.[CH2:25](Br)C=C>C1COCC1>[CH2:13]([C@@:10]1([CH3:25])[C:11](=[O:12])[N:8]([Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[C@@H:9]1[C:14]([OH:16])=[O:15])[CH:18]=[CH2:19]
Reactant: C=CCBr
Reactant: CC(C)[N-]C(C)C
Reactant: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 47 (0.200 g, 0.823 mmol) in THF (5 ml) at −78° C. was added a solution of LDA (1.10 ml, 2.4 eq.). The reaction solution was stirred for 20 min. at that temperature, warmed to −20° C. and allyl bromide (0.138 Ml, 2.0 eq.) was added slowly. Reaction mixture was warmed to 0° C. for 30 min. and quenched with KHSO4 (20 ml, 10%), extracted with ethyl acetate (3×). Combined organic layers were washed with brine twice and dried over MgSO4. After concentrating in vacuo, compound 48 was obtained. H1NMR (CDCl3): 0.15, 0.37 (s, 6H), 1.16 (s, 9H), 1.33 (s, 3H), 2.50 (m, 2H), 3.98 (s, 1H), 5.22 (m, 2H), 5.88 (m, 1H). C14H25NO3Si, Mol. Wt.: 283.44. Found: 284 (M+1).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]1([CH3:24])[CH2:15][CH2:14][CH2:13][CH:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:7][C:11]1([CH3:24])[CH2:15][CH2:14][CH2:13][CH:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCCC1(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC1(C)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
(Diethylamino)sulphur trifluoride (2.75 mL, 20.84 mmol) was added to a solution of tert-butyl 2-hydroxy-2-methylcyclopentylcarbamate (2.243 g, 10.42 mmol, from Step 3) in dichloromethane (40 mL) at −78° C. under nitrogen. After 4 h at −78° C., the mixture was quenched with saturated sodium bicarbonate, allowed to warm to room temperature, and extracted with dichloromethane. The dichloromethane phase was concentrated and purified by silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, to give tert-butyl 2-fluoro-2-methylcyclopentylcarbamate as brown oil (1.095 g, 48% yield). 1H NMR analysis indicated approximately 3.5:1 mixture of two diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(C(N)=O)nc3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 5-bromopyridine-2-carboxamide (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor, filtered, and the precipitate was washed with water and EtOAc and dried under vacuum to afford the title compound (75 mg). 1H NMR δ ppm 9.10 (d, 1 H) 8.34 (dd, 1 H) 8.21 (br. s., 1 H) 8.00 (d, 1 H) 7.52-7.72 (m, 3 H) 7.25 (d, 1 H) 7.00 (dd, 1 H) 3.82 (s, 3H); MS m/z 269 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[F:24])=[C:11]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:38][N:37]=[N:36][N:21]=4)=[CH:18][C:17]=3[F:24])=[C:11]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc(-c2nnn[nH]2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 5, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (example 14.2) was treated with sodium azide and triethylamine hydrochloride in DMF to give the title compound as white solid. MS: m/e=535.7 [M+H+].
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 1-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.