Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)c(C=O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82 g, 37.3 mmol) and K2CO3 (6.88 g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1:1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2.[CH:24]1(B(O)O)[CH2:26][CH2:25]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19]([CH:24]3[CH2:26][CH2:25]3)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(Br)ccc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(C2CC2)ccc1F
Yield: 323.3 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (750 mg, 0.649 mmol), cyclopropylboronic acid (139 mg, 1.62 mmol) and palladium (II) acetate gave the title compound as a white solid (727 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J=6.4 Hz, 1H), 6.97-6.78 (m, 2H), 5.19 (s, 1H), 4.65-4.57 (m, 1H), 2.66 (s, 6H), 1.85 (tt, J=5.1, 8.4 Hz, 1H), 2.00-1.17 (m, 5H), 1.71 (d, J=8.7 Hz, 6H), 0.92 (ddd, J=4.6, 6.3, 8.4 Hz, 2H), 0.62 (dt, J=4.7, 6.4 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.2, 157.8, 139.2, 139.2, 125.6, 125.5, 125.4, 116.5, 116.3, 71.3, 55.8, 54.2, 47.6, 46.7, 29.9, 29.6, 28.6, 25.6, 24.8, 19.6, 15.2, 9.1 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.87 min; (M+1) 347.2. Anal. Calcd. for C20H27FN2O20.0.07 (CHCl3): C, 68.00; H, 7.70; N, 7.90. Found: C, 67.99; H, 7.86; N, 7.81.
Reaction SMILES: [Al].[Pb](Br)Br.[Cl:5][C:6](Cl)([Cl:16])[CH:7]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)O>CO>[Cl:5][C:6]([Cl:16])=[CH:7][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1
Reactant: Oc1cccc(C(O)C(Cl)(Cl)Cl)c1
Agent: Br[Pb]Br
Agent: [Al]
Solvent: CO
Product: Oc1cccc(C=C(Cl)Cl)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Aluminum (3.73 g, 0.091 mol), lead bromide (2.28 g, 0.0091 mol) and 36% HC (15.47 ml, 0.182 mol) were added to 200 ml of methanol, and 3-(2,2,2-trichloro-1-hydroxyethyl)phenol (12.57 g, 0.091 mol) obtained in Step 1 was added thereto. The mixture was stirred at 60° C. for 4 hours. The solvent was removed therefrom under a reduced pressure. Ice was added to the reaction mixture and resulting mixture was washed three times with n-hexane and ether (1:1). The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:n-hexane=1:9) to obtain the title compound (16.0 g, 93%).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Reactant: Clc1cccc(CBr)c1
Agent: Cl
Product: Clc1cccc(CN2CC=C(c3nc4ccccc4s3)CC2)c1
Yield: 44 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (200 mg, 0.8 mmol) was reacted with 3-chlorobenzyl bromide (0.1 ml, 0.8 mmol) as exemplified in Example 1. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give the title compound as a pale yellow solid (120 mg, 45%); (Found: C, 65.57; H, 4.87; N, 7.59. C19H17ClNS. 0.5H2O requires C, 65.22; H, 5.19; N, 8.01%). δH (CDCl3), 2.77 (2H, m, NCH2 CH2), 2.84 (2H, m, NCH2CH2), 3.24 (2H, m, NCH2 CH2), 3.65 (2H, s, NCH2Ar), 6.68 (1H, m, NCH2CH), 7.25 (2H, s, ArH), 7.36 (4H, m, ArH), 7.82 (1H, d, J 8.0Hz, ArH), 7.98 (1H, d, J 8.1Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:8]=1[C:9]([NH:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:10])(=O)C.Cl>CO.O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:7]([OH:6])=[C:8]([CH:30]=1)[C:9]([NH:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:10]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)NCC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cc(Cl)ccc1O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.7 %

Procedure:
5N Aqueous sodium hydroxide (0.1 mL) was added to a solution of 2-acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}methyl)benzamide (83.7 mg, 0.17 mmol) in methanol/tetrahydrofuran (2 mL+1 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) and washed with n-hexane under suspension to give the title compound (47.7 mg, 63.7%) as a white crystal.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2C=CC=C[CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=O.NC1C=C2C(=CC=1)C(=O)[O:32]C2.CC(C)(C=C)CC(=O)C(O)=O>>[CH3:17][C:16]([CH3:24])([CH:18]=[CH2:19])[CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]1[CH:2]=[C:3]2[C:8]([CH2:6][O:5][C:4]2=[O:32])=[CH:9][CH:10]=1)=[O:26]
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: C=CC(C)(C)CC(=O)C(=O)O
Product: C=CC(C)(C)CC(=O)C(=O)Nc1ccc2c(c1)C(=O)OC2

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4,4-dimethyl-2-oxo-5-hexenoic acid, melting point 103-104° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][S:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[S:23])[CH:20]=1)=[O:12])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:38](Cl)(Cl)=[O:39]>ClCCl.C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][S:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([N:21]=[C:22]2[N:24]3[N:25]([CH2:26][CH2:27][CH2:28][CH2:29]3)[C:38](=[O:39])[S:23]2)[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1COCC1OC(=O)CSc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1COCC1OC(=O)CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl

Procedure:
In 15 ml of dichloromethane was dissolved 1.48 g of 1-(5-(4-acetoxytetrahydrofuran-3-yloxycarbonylmethylthio)-4-chloro-2-fluorophenylaminothiocarbonyl)hexahydropyridazine, followed by addition of 0.59 g of pyridine, which was then cooled in an ice-cold bath. Under stirring, 3.3 g of a 26.8% solution of phosgene in toluene was added dropwise, and after addition was completed, the resulting product was stirred at room temperature for 3 hours. The reaction mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=1/1), to obtain 1.20 g of a compound (No. 26) described in Table 1 (77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14](=O)[CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:15])[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:9]=32)=[CH:5][CH:4]=1
Reactant: CC(O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(cc(C)n1CC(C)O)C2
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A solution of 1.8 g of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.48 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene were added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 3 hours, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.37 g (65%) of (RS)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 110°.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22](O)[CH3:23]>ClC(Cl)C.CC1C=CC(CN)=CC=1>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH2:6][C:5]3[CH:20]=[CH:21][C:22]([CH3:23])=[CH:3][CH:4]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: CCO
Agent: Cc1ccc(CN)cc1
Solvent: CC(Cl)Cl
Product: Cc1ccc(CNC[C@@H](O)COc2cccc(-c3noc4cc(F)ccc34)c2)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 4-methylbenzylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS=89%, [M+H]+=407.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:30][C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)=[N:31][C:7]=3[C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: COc1ccc(CC(=N)N)cc1
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(Br)ccc2NC(=O)C3)cc1
Yield: 99 %

Procedure:
Analogous to Scheme 1, from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 99%. White solid, m/z (ISP) 410/412 (MH).
Reaction SMILES: CS(O[CH:6]([C:10]1[C:11]([CH:16]([CH3:18])[CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1)[CH:7]([CH3:9])[CH3:8])(=O)=O.[CH3:19][NH2:20]>C(O)(C)C>[CH3:19][NH:20][CH:6]([C:10]1[C:11]([CH:16]([CH3:18])[CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CN
Reactant: CC(C)c1ncncc1C(OS(C)(=O)=O)C(C)C
Solvent: CC(C)O
Product: CNC(c1cncnc1C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
10.6 g (39 mmol) of 5-(1-methylsulfonyloxy-2-methylpropyl)-4-isopropylpyrimidine was dissolved in 50 ml of isopropyl alcohol, and 10 ml (129 mmol) of a 40% methylamine aqueous solution was added, followed by stirring at room temperature for 8 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and 100 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent=ethyl acetate) to obtain 2.9 g (yield: 36%) of 5-[1-(N-methylamino)-2-methylpropyl]-4-isopropylpyrimidine as slightly yellow crystals (melting point: 37-39° C.).
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.[Na]>ClCCl>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2
Reactant: CC(C)C=O
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2CC(C)C

Procedure:
To the material isolated in Step A in 2 mL of dichloromethane was added 0.041 mL (0.90 mmol) of iso-butyraldehyde, followed by 0.026 mL (0.45 mmol) of acetic acid and 0.10 g (0.45 mmol) of sodium tracetoxyborohydride. After 16 h at ambient temperature the reaction was diluted with 30 mL of dichloromethane and washed twice with equal volumes of saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative reversed phase BPLC afforded the tide compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:55](O)=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C.C(OCC)(=O)C.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:37][C:55](=[O:56])[C@H:50]([C:51]([CH3:53])([CH3:52])[CH3:54])[NH:49][C:47]([O:46][CH3:45])=[O:48])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under an argon atmosphere, 294 mg of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113.5 mg (0.60 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF at 0° C. and the mixture is stirred at room temperature for 18 hours. Water and ethyl acetate are added; the aqueous phase is separated off and extracted a further 2× with ethyl acetate. The organic phases are washed 2× with water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/THF 4:1) and precipitation with hexane from a concentrated solution in methylene chloride yield the title compound: HPLC20-100 : tRet =14.5; FAB MS (M+H)30 =697.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16].[Li+].[OH-].O>C1COCC1>[Cl:16][C:6]1[CH:7]=[C:8]([Cl:15])[CH:9]=[C:10]([C:11]([F:13])([F:14])[F:12])[C:5]=1[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)Cc1c(Cl)cc(Cl)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1c(Cl)cc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,4-dichloro-6-trifluoromethylphenylacetic acid methyl ester (0.93 mmol) in 3 mL THF was added an aq. solution of LiOH (2.8 mmol, 2M). After stirring at RT for 3 days, water was added and the mixture was extracted twice with EtOAc. The aqueous phase was acidified to pH 2-3 with 1N HCl solution and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.B(Br)(Br)[Br:22]>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6]([Br:22])[N:5]=[CH:4][N:3]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(NC(=O)c2c(N)ncnc2Cl)cc1F
Solvent: ClCCl
Product: Nc1ncnc(Br)c1C(=O)Nc1ccc(O)c(F)c1
Yield: 37.5 %

Procedure:
4-Amino-6-chloro-N-(3-fluoro-4-methoxyphenyl)pyrimidine-5-carboxamide (675 mg, 2.28 mmol) was treated with boron tribromide (1M in dichloromethane, 6.80 ml, 6.80 mmol) and using dichloromethane (10 ml) as a solvent according to the method described in Example 23. The solid residue (280 mg, 38% yield) was used in the next synthetic step without further purification. Purity 99%.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([F:24])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:24])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 118, 305.4 mg, 0.87 mmol) in methylene chloride (8.7 mL) at 25° C. was treated with a 1.0M solution of boron tribromide in methylene chloride (8.75 mL, 8.75 mmol). This solution was stirred at 25° C. for 5 h. At this time, the reaction was cooled to 0° C. and quenched by the dropwise addition of a dilute aqueous ammonium hydroxide solution. The resulting solution was stirred at 0° C. for 15 min. This mixture was then poured into water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide (212.7 mg, 72.5%) as a white solid: mp 199-201° C.: EI-HRMS m/e calcd for C17H19FN2O2S (M+) 334.1151 found 334.1152.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.Br[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC1C2CCC3C4CC=C5CC(N(C)c6ccc(C#N)cc6)CCC5(C)C4CCC32CN1C
Temperature: 100 °C
Yield: 46.6 %

Procedure:
Compound 7B (20 mg, 0.058 mmol), 4-bromobenzonitrile (16 mg, 0.088 mmol), tris(dibenzylideneacetone)dipallidium (2.1 mg, 0.0023 mmol), racemic-2,2′- bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (2.2 mg, 0.0035 mmol), cesium carbonate (29 mg, 0.088 mmol) and toluene (1 mL) were mixed and heated at 100° C. overnight. The reaction mixture was cooled, quenched with water, and extracted with dichloromethane 3×. Combined organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product, which was then purified on silica gel column which was eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (12 mg, 46% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[C:19]([OH:25])=[CH:20][CH:21]=[C:22]([F:24])[CH:23]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)(=[O:10])=[O:9].CC1C=CC(S(O[C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc(-c2cc(F)ccc2O)cc1F
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2cccc(F)c2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 11 step (vii) using the product of step (iv) and the product of example 11 step (vi).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.[CH3:29][O-:30].[Na+]>CO.[Cu]I>[CH2:17]([CH:16]([C:15]1[N:10]2[N:9]=[C:8]([CH3:22])[C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[O:30][CH3:29])=[C:11]2[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: C[O-]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Br)c(C)nn12
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3OC)c(C)nn12
Temperature: 25 °C
Yield: 13.8 %

Procedure:
Stir a mixture of 3-(4-bromo-2-morpholin-4-yl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (162 mg, 0.35 mmol), sodium methoxide (57 mg, 1.05 mmol) and copper(I) iodide (67 mg, 0.35 mmol) in methanol (3 mL) in a sealed 4-mL vial for 15 h at 120° C. Cool to room temperature, remove the solid by filtration, and concentrate the filtrate under vacuum. Purify the residue by flash chromatography, eluting with hexanes/THF (10/2). Recrystallize the material from methanol to give the title compound (20 mg). ES/MS m/z 416.0 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:17])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Cl)nc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)nc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (4.68 g) and triethylamine (3.5 ml) in THF (50 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (1.84 ml). The reaction mixture was then stirred at room temperature for 2.5 hours to afford a yellow suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (10 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (15.6 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 15 min and then poured into EtOAc and washed sequentially with water and with saturated brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-chloropyridin-3-yl)morpholine-4-carboxylate (1.16 g, 26%) as a yellow solid. MS (ISP): 301.2 ([{37Cl}M+H]+), 299.1 ([{35Cl}M+H]+), 245.2 ([{37Cl}M+H—C4H8]+), 243.2 ([{35Cl}M+H—C4H8]+).