Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH:7]=1
Reactant: CCCC(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCC(=O)c1cc(Br)ccc1F
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of 1-(5-bromo-2-fluoro-phenyl)-butan-1-ol (6.2 g, 25 mmol) in dry CH2Cl2 (60 mL) were added pyridinium dichromate (19.0 g, 50.3 mmol) and molecular sieves powder (1.24 g) at room temperature and stirred overnight. The reaction mixture was filtered through diatomaceous earth and washed with diethyl ether (200 mL). The combined CH2Cl2 and ether layers were dried over anhydrous Na2SO4, filtered and concentrated to give a crude product, which was purified by column chromatography using 5% ethyl acetate/pet-ether as eluents to afford 1-(5-bromo-2-fluorophenyl)butan-1-one (4.6 g, 75%) as a syrup. 1H NMR (CDCl3): δ 8.0 (m, 1H), 7.5-7.6 (m, 1H), 7.0 (t, 1H), 2.9-3.0 (m, 2H), 1.7 (q, 2H), 1.0 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[Si:9]([O:16][C@H:17]1[CH2:26][C@H:25](O)[C@H:24]2[C:19]([CH:20]=[CH:21][C@H:22]([CH3:45])[C@@H:23]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:31]2)=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][C@H:17]1[CH2:26][C@H:25]([O:5][C:4](=[O:6])[C:3]([O:2][CH3:1])([CH3:8])[CH3:7])[C@H:24]2[C:19]([CH:20]=[CH:21][C@H:22]([CH3:45])[C@@H:23]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH2:31]2)=[CH:18]1)([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:11])[CH3:10]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: COC(C)(C)C(=O)O
Product: COC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 70.7 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 860 mg of 2-methoxy-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 836 mg of the title compound as a colorless foam.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([OH:24])=O.C([O-])(=O)C.[NH4+]>CS(C)=O>[F:37][C:31]1[CH:32]=[C:33]([I:36])[CH:34]=[CH:35][C:30]=1[NH:29][C:25]1[CH:26]=[N:27][CH:28]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[C:21]=1[C:22]([NH2:3])=[O:24]
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
1,1′-carbonyldiimidazole (70 mg, 0.43 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid (130 mg, 0.29 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Ammonium acetate (89 mg, 1.15 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (78 mg, 60%). LC-MS (M+H=452, obsd.=452).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:21]=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C=O)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOC(=O)C(CO)c1ccc(OCc2ccccc2)c(OC)c1
Yield: 115.1 %

Procedure:
A solution of ethyl 2-(4-benzyloxy-3-methoxyphenyl)-3-oxo-propionate (1.356 g; 3.47 mmol; from step (ii) above) in MeOH:CH2Cl2 (3:1, 20 mL) was cooled to −15 to −5° C., and NaBH4 (0.264 g; 6.95 mmol) was added in portions. The cooled reaction mixture was stirred, whereafter it was allowed to attain room temperature. Water was added, and the mixture was partially concentrated. After extraction with EtOAc (2×25 mL), washing of the organic phase with brine, drying (NaSO4) and evaporation, 1.32 g (97.1%) of the sub-title compound was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O>[Cl:21][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]([O:16][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:15])=[CH:12][C:11]=1[S:17](=[O:19])(=[O:18])[NH2:20]
Reactant: CCOC(=O)CBr
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A mixture of furosemide (ONBIO Inc., 20 g, 60.5 mmol), K2CO3 (8.3 g, 60.5 mmol) and ethyl bromoacetate (10.1 g, 6.7 mL, 60.5 mmol) in dry acetone (400 mL) was stirred at room temperature for 16 hours. The solvent was evaporated at reduced pressure. The residue was diluted with CH2Cl2, the solid K2CO3 was removed by filtration. The filtrate was washed with water, brine and dried over Na2SO4. The residue obtained after evaporation of the solvent was dried under vacuum to give the title compound (23.5 g, 93% yield) as a white foam. Mp 46° C. 1H NMR (300 MHz, d6-DMSO) δ 8.48 (s, 1H), 8.37 (br t, J=5.6 Hz, 1H), 7.62 (s, 1H), 7.39 (br s, 2H), 7.14 (s, 1H), 6.37-6.43 (m, 2H), 4.93 (s, 2H), 4.62 (br d, J=5.7 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.19 (br t, J=14.1 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 167.6, 165.8, 152.2, 151.1, 142.8, 137.0, 133.0, 127.1, 114.1, 110.5, 107.7, 106.3, 61.2, 61.0, 14.0. Mass spectrum (API-TIS) m/z 417 (MH+), 434 (MNH4+). Anal. calcd for C16H17ClN2O7S: C, 46.10; H, 4.11; N, 6.72. Found: C, 46.13; H, 3.97; N, 6.47.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[C:10]([C:18]([OH:20])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.O.[NH2:28][NH2:29]>ClCCl.C(OCC)C>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[C:10]([C:18]([NH:28][NH2:29])=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: NNC(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Reaction time: 2 h

Procedure:
To a suspension of 1-cyclohexylmethyl-7-chloro-1H-indole-3-carboxylic acid (as prepared in Example 16; (2.0 g, 6.8 mmol) in dichloromethane (60 ml) was added oxalyl chloride (1.2 ml, 14 mmol) and the reaction stirred for 2 h and left to stand overnight. The solvent and excess reagent was removed in vacuo. The resulting residue was dissolved in dichloromethane (10 ml) and added dropwise to a cooled solution (ice/methanol bath) of hydrazine hydrate (1.7 ml, 34 mmol) in diethyl ether (60 ml) over 5 mins. The reaction mixture was then stirred for a further 40 mins before being reduced to half its volume in vacuo and filtered. The filtrate was concentrated further and the resulting precipitate filtered. The precipitates were combined and dried in vacuo to afford 1-cyclohexylmethyl-7-chloro-1H-indole-3-carboxylic acid hydrazide (2.3 g, 7 mmol).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][N:3]1[C:13](Cl)=[O:14].[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=3)[CH:23]=2)[CH:19]=[N:18]1>C(Cl)Cl>[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:13]([N:3]4[CH2:4][CH2:5][N:6]([CH:7]5[CH2:12][CH2:11][O:10][CH2:9][CH2:8]5)[C:2]4=[O:1])=[O:14])=[N:33][CH:34]=3)[CH:23]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ncn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A 0° C. solution of Example B2 (0.14 g, 0.60 mmol) in DCM (3 mL) was treated drop-wise with a solution of 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.08 g, 0.30 mmol) and TEA (0.1 mL, 0.9 mmol) in DCM (2 mL), warmed to RT and stirred for 2 h. The mixture was concentrated to dryness, purified via silica gel chromatography (MeOH/DCM), treated with Et2O and the resulting solid collected via filtration to afford N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (93 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1 H), 8.62 (d, J=1.1 Hz, 1 H), 8.46 (s, 1 H), 8.22 (m, 1 H), 8.16 (d, J=0.7 Hz, 1 H), 8.04 (d, J=9.0 Hz, 1 H), 7.74 (dd, J=9.0, 2.9 Hz, 1 H), 7.42 (d, J=1.1 Hz, 1 H), 3.89 (s, 3 H), 4.00-3.70 (m, 5 H), 3.42-3.39 (m, 4 H), 1.76-1.65 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 465.2 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[C:5]([CH2:20][CH2:21][CH3:22])=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CCCc1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: CCCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12

Procedure:
Compound 35 was prepared via demethylation of 34 with Pyr-HCl: Mp=178-180° C.; 1H NMR (DMSO-d6) δ 9.81 (br s, 1 H), 9.02 (br s, 1 H), 7.67 (d, 2 H, J=8.5 Hz), 6.98 (s, 1H), 6.87 (d, 2 H, J=8.5 Hz), 6.71 (d, 1 H, J=2.1 Hz), 6.51 (d, 1 H, J=2.1 Hz), 2.84 (t, 2H, J=7.8 Hz), 1.75 (q, 2 H, J=7.4 Hz), 0.96 (t, 3 H, J=7.4 Hz); MS 269 (M+H)+
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1CCNC1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Agent: CCOP(=O)(C#N)OCC
Product: O=C(c1cc2c(O)cccc2s1)N1CCCC1
Yield: 92 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)-benzo(b)thiophene-2-carboxylic acid (3.0 g), pyrrolidine (0.75 g) and diethyl cyanophosphate (2.5 g), 1-(4-hydroxybenzo(b)-thiophene-2-carbonyl)pyrrolidine (2.4 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.0 g), the title compound (0.45 g) was obtained as brown crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@@H:25]([OH:28])[C:24]([CH3:30])([CH3:29])[CH2:23]1>C1COCC1>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:23][C:24]1([CH3:30])[CH3:29]
Reactant: CC1(C)C[C@@H](N)CC[C@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 equiv.) and DIEA (3.0 equiv) in THF (0.05 M) was added (1R,4S)-4-amino-2,2-dimethylcyclohexanol (stereochemistry determined as described herein) (1.2 equiv.). The mixture was stirred at 50° C. overnight. After reaction completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a white solid. MS (ESI) m/z 293.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[Si:10]([O:17][C@@H:18]([CH2:22]Cl)[CH2:19][C:20]#[N:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].COCCOC.[OH-].[Na+]>CC(OC)(C)C.[Cl-].[Na+].O.CCO>[Si:10]([O:17][C@@H:18]1[CH2:19][C:20]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:21][CH2:22]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC#N
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN=C(c2cccc(F)c2)C1
Reaction time: 2 h

Procedure:
(3-fluorophenyl)magnesium bromide (203 mL, 102 mmol, 0.5 M in ether) was slowly added via syringe to a solution of (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanenitrile (9.50 g, 40.6 mmol) in MTBE (120 mL). The reaction was stirred for two hours and DME (35 mL) was slowly added over 15 minutes followed by EtOH (23 mL). After stirring overnight, brine (50 mL) and 1M NaOH (50 mL) were added and the reaction stirred for 1 hour. The reaction mixture was filtered through a pad of Celite and the collected solids were washed with EtOAc. The filtrate was washed with 1N NaOH and brine, filtered through phase-separator paper and concentrated to provide the title compound that was used directly in the next step. MS (apci) m/z=294.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]1[CH:20]2[CH2:21][C:16]3([OH:23])[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2.C(N(C(C)C)C(C)C)C>C(Cl)Cl.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH:13]1[CH:14]2[CH2:22][CH:18]3[CH2:17][C:16]([OH:23])([CH2:21][CH:20]1[CH2:19]3)[CH2:15]2)=[O:5]
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (25.2 g, 119.60 mmol) in DCM (100 mL) was added dropwise to a stirred suspension of 4-aminoadamantan-1-ol (20.00 g, 119.6 mmol) and N-Ethyldiisopropylamine (24.83 mL, 143.52 mmol) in THF (400 mL) at 20° C., over a period of 30 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (500 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2,6-dichloro-N-(5-hydroxyadamantan-2-yl)nicotinamide (20.65 g, 51%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([B:13]3[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23]O.BrC1C=CC(C2OC(C)=C(CC[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)N=2)=CC=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([B:13]3[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:22][CH2:23][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Product: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCN1CCCC1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3) using 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8). MS (m/e) 383.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].BrC1C=C(C=C(C(F)(F)F)C=1)C(O)=O>C1COCC1.S(Cl)(Cl)=O>[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15])=[O:31]
Reactant: CNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(Br)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (300 mg, 1.37 mmol, prepared according to DE10008042) in THF (3 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M solution in THF, 1.44 mL, 1.44 mmol) at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. A solution of 3-bromo-5-trifluoromethyl-benzoyl chloride (prepared by stirring 3-bromo-5-(trifluoromethyl)benzoic acid (406 mg, 1.51 mmol, CAS RN 328-67-6) in thionylchloride (3 mL) at 100° C. for 1 hour. The reaction mixture was evaporated and the residue was dissolved in 5 mL toluene and concentrated under vacuum. This procedure was repeated three times to completely remove remainder of thionylchloride) in THF (3 mL) was added at −78° C. The reaction mixture was stirred for 1 hour at this temperature and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Yellow solid (265 mg, 41%). MS (TurboSpray): m/z=470.991 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21]C)[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:23])[CH2:10][CH2:9]1.[BrH:24]>C(O)(=O)C>[BrH:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:23])[CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Agent: Br
Solvent: CC(=O)O
Product: CN1CCc2ccc(O)cc2C1C1(c2ccccc2Cl)CC1

Procedure:
1-[1-(2-Chlorophenyl)cyclopropyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.25 g, prepared as described in Example MF7) was heated on a steam bath at 100° C. in a solution of 48% hydrobromic acid (60 ml) and glacial acetic acid (60 ml) for 16 hours. The mixture was heated under reflux for 2 hours until the reaction was complete. The solvent was removed in vacuo and the residue dried by azeotropic distillation with propan-2-ol. The resulting suspension was removed by filtration and crystallised twice from ethanol to give 1-(1-(2-chlorophenyl)cyclopropyl)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, which was characterised by elemental analysis.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:3]1[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1Br
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of anhydrous CCl4 (80 ml) containing compound 62 (4.45 g, 15.4 mmol) was added (1.1 eq, 1.04 ml) Br2. After the addition, the resulting solution was stirred for 18 hours at 40° C. The reaction mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vauo. Purification by flash chromatography (diethyl ether) afforded 3-(4-bromo-5-trimethylsilanyl-isoxazol-3-yl)-pyridine (63) as an oil (4.5 g, ˜100%). 1H-NMR (400 MHz, CDCl3): δ 9.08 (d, J=2 Hz, 1H), 8.73 (dd, J=5 Hz, 2 Hz, 1H), 8.14 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.41 (m, 1H), 0.40 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C([Li])(CC)C.CCOCC.[Mg+2].[Br-].[Br-].CON(C)[C:27]([C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>CN(C)CCN(C)C.C(Cl)Cl.CC(OC)(C)C>[N:30]1[CH:31]=[CH:32][CH:33]=[N:34][C:29]=1[C:27](=[O:28])[CH2:1][N:2]([CH3:10])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CON(C)C(=O)c1ncccn1
Reactant: CN(C)C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CN(CC(=O)c1ncccn1)C(=O)OC(C)(C)C
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of tert-butyl dimethylcarbamate (57.8 g) in N,N,N′,N′-tetramethylethylenediamine (70 ml) and MTBE (485 g) was added sec-butyl lithium (1.4 M in cyclohexane, 300 ml) over 0.5 h while maintaining the temperature below −65° C. The mixture was stirred at −65° C. for 0.5 h, then magnesium bromide diethyl etherate (111.07 g) was added with an exotherm to −60° C. The resultant slurry was allowed to warm to −11° C. over 0.5 h then cooled to −72° C. The slurry was cannulated into a −72° C. solution of N-methoxy-N-methylpyrimidine-2-carboxamide (27.2 g) in methylene chloride (400 ml) with an exotherm to −60° C. and rinsed in with MTBE (25 ml). The mixture was warmed to 0° C. over 45 min then cooled to −27° C. Acetone (30.5 ml) was added. The mixture was cooled to −29° C., then a solution of acetic acid (63.7 g) in water (303 ml) was added with an exotherm to 11° C. The mixture was warmed to 20° C. and the phases separated. The organic layer was washed with saturated aq. sodium bicarbonate (250 ml) and the aqueous phases serial back extracted with MTBE (350 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to a net weight of 85 g. Toluene (200 ml) was added and the mixture concentrated to 128 g net weight. Branched octanes (205 g) was added to the cloud point, the mixture seeded and the product allowed to precipitate for 15 minutes with stirring. The slurry was cooled to −19° C. and the precipitate collected by vacuum filtration, washed with branched octanes (82 g) and dried in a nitrogen stream to afford 29.27 g of the title compound as a solid. Physical characteristics are as follows: 1H NMR (400 MHz, CDCl3) δ 1.38, 1.49, 3.00, 4.83, 4.92, 7.50, 8.94; 13C NMR (100 MHz, CDCl3) δ 28.11, 28.30, 35.57, 35.71, 56.11, 56.61, 79.96, 123.25, 123.36, 157.56, 157.65.