Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:31](Cl)=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([F:33])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1(B(O)O)[CH2:36][CH2:35]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:31]([CH:34]3[CH2:36][CH2:35]3)=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([F:33])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 100 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
A mixture of tert-butyl 4-(1-benzhydrylazetidin-3-yloxy)-5-chloro-2-fluorobenzoate (700 mg, 1.50 mmol), cyclopropylboronic acid (258 mg, 3.00 mmol), tricyclohexylphosphine tetrafluoroborate (57 mg, 0.15 mmol), potassium phosphate (954 mg, 4.5 mmol) and palladium acetate (224 mg, 0.15 mmol) in toluene (20 mL) and H2O (1 mL) was stirred at 100° C. for 18 h. The mixture was filtered and diluted with ethyl acetate, washed with brine and concentrated. The residue was purified by silica gel chromatography (eluting with ethyl acetate/ petroleum ether from 0/10 to 1/10) to give target product (650 mg, 92%) as a yellow oil. LCMS (ESI) m/z: 474.2 [M+H].
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](O)=[C:29]([Br:36])[CH:28]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:29]([Br:36])[CH:28]=1
Reactant: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Trifluoromethanesulfonic acid t-butyldimethylsilyl ester (0.159 mL, 0.690 mmol) and triethylamine (0.120 mL, 0.863 mmol) were added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid methyl ester (158 mg, 0.574 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (203 mg, 91%).
Reaction SMILES: C(O)C.O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:23]([O-])=O)[CH:9]=[C:10]([Cl:22])[C:11]=1[O:12][CH:13]([CH3:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16].Cl>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([Cl:22])[C:11]=1[O:12][CH:13]([CH3:21])[C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])[NH2:23]
Reactant: CC(Oc1c(Cl)cc([N+](=O)[O-])cc1Cl)C(F)(F)C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(Oc1c(Cl)cc(N)cc1Cl)C(F)(F)C(F)(F)F
Yield: 86.8 %

Procedure:
4.0 g iron filings, 240 mL of a 2/1 ethanol-water mixture, and 4.86 g 3,5-dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)nitrobenzene was stirred vigorously and heated under reflux while 1.0 mL conc. HCl in 2 mL ethanol was added dropwise. After one hour 2.0 mL conc. HCl in 2.0 mL ethanol was added and reflux was maintained overnight (about 15 hours). The mixture was filtered hot through Celite. The filtrate was concentrated under vacuum before being partitioned in saturated sodium bicarbonate and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give 3.86 g of 3,5-Dichloro-4-(1-methyl-2,2,3,3,3-pentafluoropropoxy)aniline as an amber oil. 1H NMR and GC/MS confirm pure product. Anal. calcd C10H8Cl2F5NO: C, 37.06; H, 2.49; N, 4.32. Found: C, 38.71; H, 2.51; N, 4.65.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([C:26]3([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27]3)=[O:25])=[C:16]2[N:15]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([C:26]3([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]3)=[O:25])=[C:16]2[N:15]=1
Reactant: COC(=O)C1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
(R)-methyl 1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)cyclopropanecarboxylate (Example 33; 24 mg, 0.054 mmol), was dissolved in a mixture solvent of THF/MeOH/water (0.3/0.3/0.2 mL), followed by addition of lithium hydroxide monohydrate (6 mg, 0.14 mmol). After stirring at ambient temperature for five hours, the reaction mixture was diluted with water (15 mL), acidified with 1N HCl (aq.) to pH ˜3, and filtered, giving the final product as a fine white solid (19 mg, 82% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:12])=[CH:5]2.[H-].[Na+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:36][C:35]1[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=1)[C:6]([C:11]([CH:13]([CH2:25][CH2:26][CH3:27])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:12])=[CH:5]2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the title compound of Example 3 Step D (39.0 mg, 0.10 mmol) in DMF (1.0 mL) was added NaH (4.3 mg, 60% suspension in mineral oil, 0.11 mmol). After 10 min, a solution of 4-trifluoromethylbenzyl bromide (26.0 mg, 0.11 mmol) in DMF (0.5 mL) was added, and the reaction mixture was stirred for 18 h, whereupon it was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc, and the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10%, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=4.65 min, m/z 542.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 2H), 7.71 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.33-7.23 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 5.88 (ABq, J=16.5 Hz, Δν=86 Hz, 2H), 3.91 (s, 3H), 3.69 (dddd, J=9.0, 9.0, 5.5, 5.5 Hz, 1H), 3.10 (dd, J=13.5, 9.0 Hz, 1H), 2.85 (dd, J=13.5, 5.5 Hz, 1H), 1.79-1.74 (m, 2H), 1.58-1.53 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]3)[C:5]=2[CH:4]=1
Reactant: CC(=O)Cl
Reactant: OCCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Product: CC(=O)OCCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 49.2 %

Procedure:
Using the procedure of Example XXXV, 18.7 g (0.04 mole) of 2-trifluoromethyl-10-[3-(4-{3-hydroxypropoxy}-piperidino)-propyl]-phenothiazine (prepared in Example XVIII) and 3.14 g (0.04 mole) of acetyl chloride were reacted to obtain 10 g (49% yield) of 2-trifluoromethyl-10-[3-(4-{3-acetoxypropoxy}-piperidino)-propyl]-phenothiazine as a clear amber oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:19][O:20][NH:21][CH3:22]>>[CH3:19][O:20][N:21]([CH3:22])[C:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Reactant: CNOC
Product: CCc1cc(-c2ccc(C(=O)N(C)OC)s2)c(C)[nH]c1=O
Yield: 85 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and methoxy-methylamine to afford the title compound (85% yield). LC/MS: RT 2.64 min; m/e 307 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:13]([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:13]([C:14]2[S:33][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[N:17][N:16]=2)=[CH:12][CH:11]=1
Reactant: COCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1CCOC1
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Yield: 165.2 %

Procedure:
A mixture of N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N′-(4-methoxycarbonylbenzoyl)hydrazine (193.4 g) and phosphorus pentasulfide (113.34 g) in tetrahydrofuran (2.5 L) was heated to reflux for 1 hour then cooled to room temperature and poured into water (7 L). The resulting precipitate was collected by filtration, washed thoroughly with water then partially dried. The solid was added to 1:1 CH3CN—H2O (200 ml), sitrred then filtered. This procedure was repeated a further 2 times, and the resulting yellow powder washed thoroughly with acetonitrile (500 ml×5) then dried under hi-vacuum at 50° C. to give methyl 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoate (179.6 g) as a yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]#[N:16])[CH:10]=[N:11][CH:12]=1.[H][H]>[Ni].N.CO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:11][CH:12]=1
Reactant: [H][H]
Reactant: CN1CCC[C@H]1c1cncc(CCC#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1CCC[C@H]1c1cncc(CCCN)c1
Yield: 88.4 %

Procedure:
(S)-3-(5-(1-Methylpyrrolidin-2-yl)pyridin-3-yl)propanenitrile (preparation 3) (140 mg, 0.65 mmol) and Raney nickel (50 mg) in 20% ammonia in MeOH (50 mL) were stirred under 50 psi hydrogen at 50° C. for 4 hours. The reaction mixture was filtered through Celite then the solvent evaporated. The crude product was purified by flash chromatography (7% [20% ammonia in MeOH] in DCM) to give the title compound as a pale yellow oil (126 mg, 88%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[NH4+:13]>C1COCC1>[Cl:10][C:8]1[CH:9]=[C:5]([C:3]([NH2:13])=[O:4])[NH:6][CH:7]=1
Reactant: O=C(c1cc(Cl)c[nH]1)C(Cl)(Cl)Cl
Reactant: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)c[nH]1
Yield: 92 %

Procedure:
A solution of 2,2,2-trichloro-1-(4-chloro-1H-Pyrrol-2-yl)ethanone (14.0 g, 56.7 mmol) in THF (100 mL) was bubbled with ammonium gas for 2 h at room temperature. TLC analysis indicated that there was complete conversion of starting material. The reaction mixture was concentrated in vacuo to yield 7.5 g of the above compound (51.88 mmol, yield 92%). 1H-NMR (Acetone-d6) δ 10.92 (br s, 1H), 7.21 (br s, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 6.57 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:34](=[O:37])[CH2:35][CH3:36]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)Cl.O>[CH3:36][C:35]([CH:34]=[O:37])=[CH:26][C:19]1[C:17]2[O:18][CH:13]([CH2:12][O:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24]
Reactant: CCC=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C=O)=Cc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 1.00 g (2.5 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin -2-yl]methyl 4-methylbenzenesulfonate, 0.35 g (2.5 mmole) of potassium carbonate and 0.31 g (1.7 mmole) of benzyltrimethylammonium chloride in 5 mL of methylene chloride was added 0.145 g (2.5 mmole) of propionaldehyde. The mixture was stirred at room temperature under nitrogen for 15 hours, then diluted with 100 mL of water and extracted twice with 100 mL portions of methylene chloride. The combined organic extracts were washed with 100 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 0.50 g of the (R)-enantiomer of toluene-4-sulfonic acid 8-(2-methyl-3-oxo-propenyl)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester as a yellow oil. This was dissolved in a mixture of 12 mL of acetic acid and 8 mL of ethanol and 0.32 g (5.7 mmole) of iron powder was added. The mixture was refluxed for eight hours under nitrogen. The solvent was then removed in vacuum and replaced with 250 mL of ethyl acetate. This mixture was washed with 250 mL portions of saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. Column chromatography on silica gel with chloroform as eluant gave 0.22 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet (m-coupling) 8.6 δ (1 H); doublet (m-coupling) 8.0 δ (1 H); doublet 7.76 8 (2 H); doublet 7.57 δ (1 H); doublet 7.24 δ (1 H); doublet 7.20 δ (2 H); multiplet 4.55 δ (1 H); doublet of doublets 4.3 δ (1 H); multiplet 4.2 δ (2 H); doublet of doublets 4.15 δ (1 H); singlet 2.5 δ (3H); singlet 2.4 δ (3 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])=[CH:5]3)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Reactant: OC1CCN(Cc2ccccc2)CC1
Product: O=C(c1cc2cc(OC3CCN(Cc4ccccc4)CC3)ccc2[nH]1)N1CCOCC1

Procedure:
According to the procedure described for the synthesis of Example 1/Step 2 the tide compound was synthesized from (5-hydroxy-1H-indol-2-yl)-morpholin-4-yl-methanone (Example 1, Step 1) and 1-benzyl-4-hydroxy-piperidine (commercially available). (m/e): 419.52 (MH+, 100%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([NH:11][C:12]2[C:13]3[C:17]([CH:18]=[C:19](B4OC(C)(C)CC(C)(C)O4)[CH:20]=2)=[N:16][N:15](C2CCCCO2)[CH:14]=3)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].Br[C:38]1[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]2[C:39]=1[CH:40]=[CH:41][NH:42]2.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].CC#N>O1CCOCC1.O.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[C:47]([C:45]1[CH:44]=[C:43]2[C:39]([CH:40]=[CH:41][NH:42]2)=[C:38]([C:19]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:11][C:9]([C:8]3[N:4]([CH:2]([CH3:3])[CH3:1])[N:5]=[CH:6][CH:7]=3)=[O:10])[CH:20]=2)[CH:46]=1)#[N:48]
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cc(C#N)cc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 1 h
Yield: 15.6 %

Procedure:
1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (49 mg, 0.1 mmol) was dissolved in 1,4-Dioxane (0.4 mL) and added to 4-bromo-1H-indole-6-carbonitrile (22 mg, 0.1 mmol, available from Sinova) in a microwave vessel. 1,4-Dioxane (0.4 ml) was added followed by chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (Solvias catalyst, 2 mg, 0.004 mmol, (heaped microspatula) available from ABCR) and a solution of potassium triphosphate (0.2 g, 0.1 mmol) in water (0.2 ml). The vessel was sealed and heated in CEM Discover using initial 150 W to 110° C. for 20 min. After cooling the solution was loaded onto a C18 SPE cartridge (pre-conditioned with MeCN/0.1% TFA) and flushed through with a further 3 ml MeCN/0.1% TFA. Solvent was removed by blowdown under a stream of nitrogen. The residue was dissolved in MeOH (0.5 ml) and loaded onto a SCX-2 SPE cartridge (1 g) pre-conditioned with MeOH. The material was left on the column for 1 hr then eluted with 2M ammonia/MeOH and evaporated to dryness. The sample was purified by Mass Directed AutoPrep (Method C) to afford the title compound (6.4 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6](Cl)[N:7]=1.[F:10][C:11]1[CH:12]=[C:13]([SH:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([S:21][C:13]2[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([F:10])[CH:12]=2)[N:7]=1
Reactant: Fc1cc(S)cc(C(F)(F)F)c1
Reactant: Clc1nnc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cc(Sc2nc(Cl)nnc2Cl)cc(C(F)(F)F)c1

Procedure:
To a solution of 3,5,6-trichloro-1,2,4-triazine (3 mmol) in dry THF (30 mL) at −78° C. under nitrogen atmosphere is added 3-fluoro-5-(trifluoromethyl)benzenethiol (3 mmol) and sodium carbonate (3 mmol). The reaction is allowed to reach room temperature and is stirred at room temperature until formation of the desired compound. The solvent is evaporated. The residue is suspended in water and extracted with CH2Cl2. The dichloromethane solution is dried over MgSO4 and evaporated. The residue is chromatographed on a silica gel column.
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][C@H:8]([C:13](=[O:33])[NH:14][C@H:15]([B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:31])[CH3:30])[O:21]1)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[C:35]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)C(O)=O)[CH:36]=1>>[CH3:18][CH:17]([CH3:19])[CH2:16][C@H:15]([NH:14][C:13](=[O:33])[C@@H:8]([NH:7][C:6](=[O:34])[C@@H:42]([NH:41][C:37]1[CH:36]=[C:35]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:40]=[CH:39][CH:38]=1)[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:30])[CH3:31])[O:21]1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1

Procedure:
The title compound is prepared as described in example 1 but using {(S)-3-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-butyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][O:22]C(C4C=CC=CC=4)(C4C=CC(OC)=CC=4)C4C=CC(OC)=CC=4)[C@@H:17]([OH:18])[CH2:16]3)[CH:13]=[N:14][C:7]=12.[C:46](OC(=O)C)(=[O:48])[CH3:47].O>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([O:18][C:46](=[O:48])[CH3:47])[CH2:16]3)[CH:13]=[N:14][C:7]=12
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(-c5cccs5)ccnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(-c4cccs4)ccnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
Compound 7 (124 mg, 0.20 mmol) was azeotroped three times with anhydrous pyridine. This was dissolved in anhydrous pyridine (2.0 ml), and 38 μl (0.40 mmol) of acetic anhydride was further added thereto. The resulting mixture was stirred at room temperature for 2 days. The mixture was poured into water (50 ml) and extracted with methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml anhydrous methylene chloride, and 200 μl dichloroacetic acid was added thereto at 0° C. After stirring at 2° C. for 15 minutes, the mixture was poured into 8 ml saturated aqueous sodium bicarbonate, diluted with 42 ml water, and then extracted with methylene chloride (50 ml×3). After drying over Na2SO4, the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel chromatography using methylene chloride:ethyl acetate (9:1 to 3:2) as an elution solvent to give 65 mg of Compound 9 in a yield of 88%.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[CH:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.x) (178 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (86 mg, 0.5 mmol) according to general procedure II. Obtained as a dark red solid (70 mg, 31%). MS (EI) 448.1 [(M+)+]; mp 225° C.