Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[C:30]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:30])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1ccccc1NCCN(C)Cc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45.2 %

Procedure:
To a solution of (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone (Example 1; 0.032 g, 0.081 mmol) in DMF (0.8 mL) was added K2CO3 (0.022 g, 0.16 mmol) and iodomethane (0.03 g, 0.2 mmol), and the resulting suspension was stirred at 25° C. for 45 min. The suspension was partitioned with EtOAc (20 mL) and H2O (20 mL), and the organic layer was washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (2% CH3OH/CH2Cl2) to provide a colorless oil (0.015 g, 47%). MS (ESI): mass calculated for C26H35N3O2, 409.27; m/z found, 410.5 [M+H]+, 432.4 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.46 (d, J=7.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.27-7.25 (m, 1H), 6.84 (dt, J=7.8, 1.3 Hz, 1H), 6.78 (dt, J=7.8, 1.3 Hz, 1H), 6.63 (dt, J=7.8, 1.6 Hz, 1H), 6.58 (dt, J=7.8, 1.6 Hz, 1H), 4.53 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.60 (br s, 2H), 3.31 (br s, 2H), 3.20 (t, J=6.1 Hz, 2H), 2.73 (t, J=6.1 Hz, 2H), 2.20 (s, 3H), 1.62-1.46 (m, 6H), 1.37 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9](S(C)=O)[N:8]=1.[NH:41]1[CH2:47][CH2:46][CH2:45][C@H:42]1[CH2:43][OH:44].C(N(CC)CC)C.CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9]([N:41]2[CH2:47][CH2:46][CH2:45][CH:42]2[CH2:43][OH:44])[N:8]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Reactant: OC[C@@H]1CCCN1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CCCC3CO)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine (prepared in the above (4)), L-prolinol 53 mg, triethylamine 53 mg and dimethylformamide 4 ml is stirred at room temperature for 1.5 hours and then at 65° C. for 3.5 hours. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform: ethyl acetate=1:2) to give 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine as a colorless caramel 96 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:30]=[O:32])=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C=Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg (0.70 mmol) of 4-(tetrahydropyranyloxy)methyl-2'-amino-1,1'-biphenyl (Example 1, Step N) and 0.40 mL of triethylamine in 10 mL of methylene chloride under a nitrogen atmosphere was treated with triphosgene (420 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 30 minutes when thin layer chromatography on silica (hexane/ethyl acetate; 2:1) revealed no remaining amine. The reaction mixture was evaporated under vacuum to yield the crude product which was used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.3 %

Procedure:
To a solution of 3-Hydroxybenzaldehyde (3.05 g, 24.97 mmol) in acetonitrile (15 ml) was added K2CO3 (7.6 g), followed by N-(2-chloroethyl)morpholine hydrochloride (4.65 g). The reaction mixture was stirred at room temperature for 30 minutes, then at reflux overnight. Additional N-(2-chloroethyl)morpholine hydrochloride (0.93 g) and K2 CO3 (0.7 g) were added and the mixture was refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and chloroform, the layers were separated and the aqueous layer was extracted with chloroform (2×75 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford 7.3 g of 3-[2-(4-morpholinyl)ethoxy]benzaldehyde, as an amber liquid.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:21]([O:24][C:25]([N:27]1[CH2:33][CH2:32][CH2:31][CH:30]([N:34]([C:50](=[O:52])[CH3:51])[CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:29]2[CH:53]=[CH:54][C:55](Br)=[CH:56][C:28]1=2)=[O:26])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:50]([N:34]([CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:48])([F:47])[F:49])[CH:37]=1)[CH:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25]([O:24][CH:21]([CH3:23])[CH3:22])=[O:26])[C:28]2[CH:56]=[C:55]([N:20]=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:54]=[CH:53][C:29]1=2)(=[O:52])[CH3:51]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 80 °C
Yield: 89 %

Procedure:
Combine tris(dibenzylideneacetone)dipalladium (0) (0.077 g, 0.084 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphyl (0.157 g, 0.252 mmol) and sodium t-butoxide (0.113 g, 1.18 mmol) in toluene (5 mL) and purge this suspension with nitrogen at room temperature for 5 min. Add benzophenoneimine (0.155 mL, 0.924 mmol) followed by isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.500 g, 0.840 mmol) and heat this mixture at 80° C. under nitrogen for 1 h. Cool the mixture to room temperature, dilute with dichloromethane and filter through Celite. Remove the filtrate solvent under reduced pressure and purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as an orange oil (0.520 g, 89%): APCI MS 696 (M+H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:18]([O:19]C(=O)C)[C@@H:17]([CH2:23][O:24]C(=O)C)[O:16][C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:6]1[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(=O)C.C(OCC)(=O)C.C(O)C.CCCCCC>CO.C[O-].[Na+]>[C:29]1(=[O:38])[N:28]([C@@H:6]2[C@@H:5]([OH:4])[C@H:18]([OH:19])[C@@H:17]([CH2:23][OH:24])[O:16][C@@H:7]2[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (3) (40.6 g, 84 mM) in 750 ml of dry methanol and 30 ml of 0.5M sodium methoxide was added to a 2 liter round bottomed flask equipped with magnetic stirring bar, saprum inlet and bent tube adapter and the contents stirred at room temperature for 18 hours. TLC indicated completion of the reaction. (The TLC solvent was 10:2:10 ethyl acetate: ethyl alcohol:hexane). To the mixture was added 15 g of Bio-Rad (Bio-Rad Laboratories, P.O. Box 708, 220Maple Ave., Rockville Center, N.Y. 11571) ion exchange resin AG-50W-X-8 (prewashed with H2O, methanol, and dried) and stirred for 5 minutes (pH should be ≤7.0). The mixture, after filtration followed by the removal of solvent, furnished benzyl 2-deoxy-2-phthalimido-α-D-glucopyranoside (1), 30 g (89.4% yield).
Reaction SMILES: C([Li])CCC.CN(CCN(C)C)C.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH:21]=[CH:20][C:19]=2[CH:23]=1.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C>CCOCC>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([B:28]([OH:29])[OH:27])=[CH:20][C:19]=2[CH:23]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc2occc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc2oc(B(O)O)cc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.7M, 35.16 ml) was added dropwise to a stirred solution of TMEDA (9.58 ml) and 5-methylbenzofuran (8.22 g) in ether (250 ml) maintaining the temperature below -60° C. throughout. The solution was warmed to about -10° C. over 45 minutes and stirred at this temperature for 30 minutes. A precipitate formed on warming. The suspension was cooled and triisopropylborate (43 ml) was added, maintaining the temperature below -60° C. The solution was warmed gradually to room temperature before quenching with 2N HCl (70 ml). The mixture was extracted with ether (3×50 ml) and the combined organic extracts washed with 2N HCl (4×30 ml), water (2×30 ml) and dried before evaporation to give the title compound as an orange solid (12.75 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:19])[C:4]([N:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:5].[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH:32]=O)=[CH:30][N:29]=[CH:28]2)=[CH:24][C:23]=1[F:36])#[N:21].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32][NH:2][C@H:3]([CH3:19])[C:4]([N:6]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=4)[CH:11]=[CH:10][CH:9]=3)[CH3:7])=[O:5])=[CH:30][N:29]=[CH:28]2)=[CH:24][C:23]=1[F:36])#[N:21]
Reactant: C[C@@H](N)C(=O)N(C)c1cccc2ccc(O)cc12
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NCc1cncn1Cc1ccc(C#N)c(F)c1)C(=O)N(C)c1cccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Amino-N-(7-hydroxynaphthalen-1yl)-N-methylpropionamide hydrochloride, as described above in Step D, (109 mg, 0.39 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 4, Step G, (89 mg, 0.39 mmol), were stirred in MeOH (2 mL) and was neutralized with N,N-diisopropylethylamine. Acetic acid was then added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hr at ambient temperature, then NaCNBH3 (32 mg, 0.51 mmol) was added, the solution was readjusted to ca. pH 5 by addition of AcOH, and stirring was continued for 18 hrs. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of 1% to 6% MeOH −0.1% to 0.6% NH4OH —CH2Cl2 to yield the titled product.
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[F:50][C:51]1[CH:52]=[C:53](B(O)O)[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[F:50][C:51]1[CH:52]=[C:53]([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:37])=[N:34][CH:35]=2)[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(F)cc(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 3-fluoro-5-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as brown amorphous solid. MS: 436.4 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[N:3]1([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
NaH (0.444 g, 11.1 mmol) was dissolved in anhydrous DMF (5 mL) under argon and cooled to 0° C. To it was added 1H-indole (1.00 g, 8.54 mmol) dissolved in anhydrous DMF (5 mL). The reaction was stirred for 15 min at 0° C. followed by the addition of ethyl 3-bromopropanoate (1.10 mL, 8.54 mmol). The reaction was then stirred for 3 h at 70° C. and then quenched by the addition of H2O (30 mL). The organic products were extracted with EtOAc (3×30 mL), washed with H2O (2×30 mL), brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified using automated column chromatography method 1 to yield ethyl 3-(1H-indol-1-yl)propanoate (0.759 g, 3.49 mmol). The title compound was then prepared from ethyl 3-(1H-indol-1-yl)propanoate (0.486 g, 5.52 mmol) according to General Procedure B (prep. HPLC method 1) and isolated as a white solid (0.104 g, 23%). 1H NMR (400 MHz, MeOD): δ 7.53 (d, J=7.83 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.16 (m, 2H), 7.02 (t, J=7.4 Hz, 1H), 6.41 (d, J=2.8 Hz, 1H), 4.48 (t, J=6.5 Hz, 2H), 2.56 (t, J=6.6 Hz, 2H). ESI-LRMS: [M+H]+=205.1 m/z. ESI-HRMS: calc. for C11H12N2O2: [M+H]+=205.0972 m/z, found: [M+H]+=205.0971 m/z.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[CH:35][C:34]([CH3:38])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(C)cc21
Temperature: 25 °C
Yield: 43.8 %

Procedure:
Purge a mixture of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.400 g, 0.672 mmol), trimethylboroxine (0.084 g, 0.672 mmol), and potassium carbonate (0.279 g, 2.02 mmol) in anhydrous tetrahydrofuran (5 mL) with nitrogen, then add tetrakis(triphenylphosphine)palladium (0) (0.077 g, 0.067 mmol) and stir at reflux for 1 h. Cool the mixture to room temperature and dilute with ethyl acetate (30 mL) and wash with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (20:1 to 3:1), to provide the title compound as a white solid (0.156 g, 44%): ESI MS 531 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][P:5]1(=[S:14])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1.C(N(CC)CC)C.Cl[S:24][N:25]([CH3:29])[C:26]([F:28])=[O:27]>O1CCCC1.CCOCC>[CH3:29][N:25]([S:24][N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[P:5]1(=[S:14])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1)[C:26]([F:28])=[O:27]
Reactant: CC(C)CNP1(=S)Oc2ccccc2O1
Reactant: CN(SCl)C(=O)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CN(SN(C)C(=O)F)P1(=S)Oc2ccccc2O1
Reaction time: 1.5 h

Procedure:
A solution of N-(2-methylpropyl)-2-thioxo-1,3,2-benzodioxaphosphol-2-amine (17.2 g, 70.8 mmol) and triethylamine (9.8 ml, 70.8 mmol) in tetrahydrofuran (50 ml) is added dropwise over 10 minutes to a solution of N-chlorothio(methyl)carbamoyl fluoride (10.2 g, 70.8 mmol) in tetrahydrofuran (50 ml) cooled in an ice bath. After the addition the mixture is stirred for 1.5 hours at 0°, diluted with ether (200 ml), washed with ice cold water, dried over sodium sulfate and concentrated under reduced pressure. The residue shows identical absorptions in the ir and pmr spectra for νC=O and N--CH3 as obtained for the carbamic fluoride II'" of Example 5. This crude carbamoyl flouride product is suitable for reaction with methyl N-hydroxyethanimidothioate as in Example 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27](S(C2C=CC=CC=2)(=O)=O)[CH:26]=[C:25]3[C:40]#[N:41])=[O:21])([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[C:40]#[N:41])=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]cc(C#N)c3c2)C1
Temperature: 50 °C

Procedure:
Water (1 mL) was added to a solution of 3-(1-benzenesulfonyl-3-cyano-1H-indole-5-carbonyl)-3-benzyl-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.175 mmol) in MeOH (4 mL), followed by potassium carbonate (73 mg, 0.525 mmol). The reaction mixture was heated at 50° C. for 10 minutes, then cooled to room temperature and diluted with water and brine. The resulting mixture was extracted with DCM, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30% to 50% of EtOAc in hexane) to give 3-benzyl-3-(3-cyano-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as white foamy solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][Si](C)(C)C)=[C:7]2[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CC(OC)(C)C>[C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:29])[F:28])=[CH:4][C:5]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:6][C:7]=12)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: COC(C)(C)C
Product: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.5 %

Procedure:
To a solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]-pyrimidine (Example C.1 step 3a) (13.65 g, ca. 26 mmol) in THF (40 mL) and MeOH (100 mL) at 0° C. was added K2CO3 (362 mg, 10 mol %), and the mixture was stirred at 0° C. for 6 h. Diluted with TBME and ice water, separated phases, washed organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum left a dark brown solid, which was purified by silica gel column chromatography with heptane/EtOAc 9:1 followed by trituration with heptane to give the 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[-1,5-a]pyrimidine (7.90 g, 89%) as a yellow solid. MS (ISP) 356.0 [(M+H)+]; mp 138° C.