Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.ClCCl.[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18]C)[CH:14]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:13][CH2:12]2>O>[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:13][CH2:12]2
Reactant: CCC(=O)NCCC1CCc2cc(F)c(OC)cc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(=O)NCCC1CCc2cc(F)c(O)cc21
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Boron tribromide (7.9 g, 31.5 mmols) was gradually and dropwise added to a dichloromethane (100 ml) solution of N-[2-(5-fluoro-6-methoxyindan-1-yl)ethyl]propionamide (4.18 g, 15.8 mmols) while cooling with ice. After having been stirred for 2 hours while still cooling with ice, the reaction mixture was poured into water containing ice and then stirred at room temperature for 3 hours, and the organic substance was extracted with ethyl acetate. The extract was washed with a saturated saline solution and water and then dried with anhydrous magnesium sulfate, and the solvent was removed through distillation under reduced pressure. The resulting residue was purified through silica-gel column chromatography (ethyl acetate/hexane=9/1) to obtain 3.68 g (yield: 93%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16](C(O)=O)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.O=C1C2C(=CC([C:35]([OH:37])=[O:36])=CC=2)C=CN1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([C:35]([OH:37])=[O:36])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Reactant: O=C(O)c1ccc2c(=O)[nH]ccc2c1
Product: COc1ccc(CNc2nccc3cc(C(=O)O)ccc23)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 2-5 of Intermediate 27, using 1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid. +ESI (M+H) 309.2; 1H NMR (400 MHz, CD3OD, δ): 8.37 (d, J=1.56 Hz, 1H), 8.34 (d, J=8.78 Hz, 1H), 8.12 (dd, J=8.68, 1.66 Hz, 1H), 7.67 (d, J=6.44 Hz, 1H), 7.29-7.36 (m, 2H), 7.15 (d, J=6.24 Hz, 1H), 6.86-6.93 (m, 2H), 4.73 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[CH2:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[O:54][CH3:55]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])[CH:45]([C:38]1[C:39]([O:43][CH3:44])=[CH:40][CH:41]=[CH:42][C:37]=1[O:36][CH3:35])[C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[O:54][CH3:55]
Reactant: COc1cccc(OC)c1C(O)c1c(OC)cccc1OC
Reactant: COc1cccc(OC)c1Cc1c(OC)cccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1cccc(OC)c1C(c1c(OC)cccc1OC)C(c1c(OC)cccc1OC)c1c(OC)cccc1OC
Reaction time: 1 h

Procedure:
To a solution of bis(2,6-dimethoxyphenyl)methanol (1.52 g, 0.005 mol) in acetonitrile (50 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.95 g, 0.005 mol). To the resulting deep red solution was added bis(2,6-dimethoxyphenyl)methane (1.44 g, 0.005 mol). The reaction mixture decolored within about one hour and was stirred for an additional 17 hours. The reaction was quenched by the addition of water (10 mL), extracted with dichloromethane and dried over anhydrous magnesium sulfate. Evaporation of the solvent and hot filtration using hexane/benzene gave 1,1,2,2-tetrakis(2′,6′-dimethoxyphenyl)ethane as a mixture of rotational isomers after evaporation of the solvents and washing with diethyl ether.
Reaction SMILES: [C:1]1(=[N:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-:14].[Na+]>O>[NH:11]1[C:6](=[O:14])[CH2:7][CH2:8][CH2:9][C:10]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]1=2
Reactant: ON=C1CCCc2ccccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2ccccc2N1

Procedure:
A mixture of 1.0 g (6.2 mmole) of 1-tetralone oxime and 10 g polyphosphoric acid was heated at 105° for 1 hr. The warm mixture was poured into 100 mL water with stirring. The pH was carefully adjusted to 6-7 by addition of solid sodium bicarbonate and the mixture was extracted with 60 mL ethyl ether. The organic phase was washed with 10 mL saturated sodium chloride, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from ether/hexane to give 1,3,4,5-Tetrahydro-benzo[b]azepin-2-one, 0.682 g, m.p. 141-142°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16](O)[O:15][C:14](=O)[CH:13]=2)=[CH:8][CH:7]=1.O.[NH2:20][NH2:21]>CCO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[N:21][NH:20][C:14](=[O:15])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C1C=C(c2ccc(OCCCCl)cc2)C(O)O1
Solvent: O
Solvent: CCO
Product: O=c1cc(-c2ccc(OCCCCl)cc2)cn[nH]1
Yield: 60.8 %

Procedure:
A solution of the product from example 94 step 3 (2.0 g, 7.45 mmol) and hydrazine hydrate (0.59 g, 1.5 eq.) in 20 mL of EtOH was stirred at 85° C. for 2 h. The solvent was reduced and the solid was collected and washed with cold EtOH to give 1.2 g (61%) of 5-[4-(3-chloropropoxy)phenyl)-2H-pyridazin-3-one: Mp 197-9° C.; MS m/z 265 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[O:12])[C@H:8]([CH2:18][CH2:19][NH:20][C:21](=[O:40])[CH2:22][S:23][C:24]2[N:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)=[CH:26][N:25]=2)[CH2:7]1.[Li+].[OH-].O.OS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][C@H:6]1[CH2:10][N:9]([C:11]([CH2:13][C:14]([OH:16])=[O:15])=[O:12])[C@H:8]([CH2:18][CH2:19][NH:20][C:21](=[O:40])[CH2:22][S:23][C:24]2[N:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)=[CH:28][N:29]=2)[CH2:7]1
Reactant: COC(=O)CC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CCNC(=O)CSc1ncc(-c2ccc(OC)c(OC)c2)cn1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc(SCC(=O)NCC[C@@H]3C[C@@H](Cc4ccc(Cl)c(Cl)c4)CN3C(=O)CC(=O)O)nc2)cc1OC
Temperature: 20 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
To a solution of N-(2S,4R)-[4-(3,4-dichlorobenzyl)-1-(methoxycarbonyl-methylcarbonyl)pyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylsulfanyl]-acetamide (prepared according to Example 6 above) (40 mg, 0.06 mmol) in CH3OH was added 0.3 mL of a freshly prepared 1N aqueous solution of LiOH. The solution was stirred under N2 at 20° C. for 16 hrs, after which it was poured into water, the mixture then acidified with dilute aqueous H2SO4 and extracted with EtOAc. Drying and evaporation of the organic layer then afforded 33 mg of N-(2S,4R)-[4-(3,4-dichlorobenzyl)-1-(carboxymethylcarbonyl)pyrrolidin-2-ylethyl]-2-[5-(3,4-dimethoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide (0.05 mmol) as a white amorphous foam, mass spectrum 647(MH+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.C(N(CC)CC)C.[P:16](Cl)([Cl:19])([Cl:18])=[O:17]>CCOCC>[P:16]([Cl:19])([Cl:18])(=[O:17])[O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure described by McGuigan et al., 1993, Supra, a solution of p-bromophenol (13.20 g; 76.30 mmol) and distilled triethylamine (10.65 mL) in anhydrous Et2O (165 mL) was added dropwise into a vigorously stirred solution of phosphoryl chloride (8.5 mL; 91.2 mmol) in anhydrous Et2O (83 mL) at 0° C. over a period of three hours under nitrogen atmosphere. Subsequently, the resultant mixture was gradually warmed up to room temperature, stirred efficiently overnight at room temperature and then heated to reflux for two hours. The reaction mixture was cooled to room temperature and filtered under aspirator pressure. The precipitate was washed with anhydrous Et2O (2×50 mL). The combined Et2O layers were evaporated to dryness on rotary evaporator to yield crude 4c as a pale yellow oil which was then subjected to vacuum distillation to give pure 4c (14.05 g; 63.5% yield) as a colorless viscous oil (bp. 110–115° C./2 mm Hg). IR (Neat) 3095, 1481, 1303, 1187, 948, 829 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.50 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=9.0 Hz). GC/MS (m/e) 290 (M+), 254 (M+-Cl), 173 (M+-POCl2, 81Br), 171 (M+-POCl2, 79Br), 156 (M+-PO2Cl2, 81Br), 154 (M+-PO2Cl2, 79Br).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:15]3)=[CH:9][CH:8]=2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(Oc2ccc(COCC3CCCNC3)cc2)cc1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(COCc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Yield: 57.3 %

Procedure:
Using 3-[4-(4-fluorophenoxy)benzyloxymethyl]piperidine (35.7 mg, 0.113 mmol) and 3-(methoxycarbonyl)phenylboric acid (40.7 mg, 0.226 mmol), the same procedure was followed as in Example 2 to give 29.1 mg (57%) of the desired compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CN(C=O)C.O>[CH:17]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A suspension of 3,4-dihydroxybenzaldehyde (5.0 gm, 0.0362 mol), anhydrous potassium carbonate (6.0 gm, 0.0434 mol) and cyclopentyl bromide (6.5 gm, 0.0434 mol) in dry DMF (50 ml) was heated and stirred at 80° C. for 24 hrs. Reaction mixture was then cooled and diluted with water (500 ml), acidified with 1N HCl and extracted with ethyl acetate (3×100 ml). The ethyl acetate extract was washed 5% sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The dried extract on concentration afforded a residue which was purified by silica gel chromatography using 10% ethyl acetate in petroleum ether as the eluent to provide 5.0 gm of the title product as white solid. mp: 87–89° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([S:15][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:14]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-bromopropylcarbamate (0.30 g) in N,N-dimethylformamide (5 ml) was treated with ethanethiol (0.104 ml) and potassium carbonate (0.29 g), and the mixture stirred at room temperature overnight. The mixture was partitioned between water (20 ml) and dichloromethane (30 ml), and the organic layers evaporated in vacuo to give the title compound (0.236 g).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=3[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1cc2cc(C(F)(F)F)ccc2s1)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2sc(C(Cl)C3CCCCC3)cc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of cyclohexyl[5-(trifluoromethyl)-1-benzothiophen-2-yl]methanol (860 mg) synthesized above in toluene (20 mL) was added thionyl chloride (239 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (806 mg, 89%) as a pale-brown oil
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOCC1
Temperature: 50 °C
Yield: 44.6 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (0.30 g) was heated with potassium carbonate (anhydrous, 0.46 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.16 g) in anhydrous DMF (1 mL) was added. The reaction mixture was then heated to 50° C. overnight. The reaction was quenched into water (50 mL) and extracted with ethyl acetate (50 mL, 3 times). The organic layer was combined and washed with brine (50 mL). The organic layer was separated and dried by passing through a hydrophobic frit before being evaporated under reduced pressure to give oil). This material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This material was purified by reverse phase chromatography (20-60% acetonitrile: water). This gave the title compound as a white solid (0.1279 g).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]3[O:25]C(C)(C)C(C)(C)[O:18]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CC(C)=O.O>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([B:17]([OH:18])[OH:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(B(O)O)ccc21
Temperature: 23 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To N-Boc-indole-5-boronic acid pinacol ester (172 mg, 0.500 mmol, 1.00 equiv) in acetone/H2O (5.0 mL/5.0 mL) at 23° C. was added NH4OAc (193 mg, 2.50 mmol, 5.00 equiv) and NaIO4 (535 mg, 2.00 mmol, 4.00 equiv). After stirring for 24 hr at 23° C., the reaction mixture was concentrated in vacuo to remove acetone. To the residual solution was added EtOAc (5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×5 mL). The combined organic phases are washed with brine (10 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:1 (v/v) to afford 70.0 mg of the title compound as a colorless solid (54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]([F:42])([F:41])C(OC)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[O:26][CH:36]([F:42])[F:41])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(O)c2ccccc21
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(OC(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of example 145, Cs2CO3 (2 eq) in DMF (0.2M) was heated at 100° C. (open flask) then methyl chlorodifluoroacetate (2 eq) was added and the mixture stirred at 90-110° C. for 3 h. After cooling to rt, the mixture was diluted with water, extracted with ethyl acetate and the solvent evaporated. The residue was purified by crystallisation in hexane\ether to give the title compound as a white powder.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1CC=C(C2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)CC1>>[CH3:1][CH:2]([CH3:4])[CH2:3][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: CC(C)C=O
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Agent: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Product: CC(C)CN1CCC(Oc2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 429, substituting isobutyraldehyde for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.49-8.60 (m, 2H) 8.09 (s, 1H) 7.68-7.80 (m, 2H) 7.10 (d, J=5.19 Hz, 1H) 6.96-7.04 (m, 2H) 4.85 (s, 4H) 4.21-4.28 (m, 1H) 2.65-2.79 (m, 2H) 2.13-2.24 (m, 2H) 2.06 (m, 2H) 1.98 (s, 2H) 1.77-1.88 (m, 2H) 1.67-1.77 (m, 1H) 0.89 (d, J=6.71 Hz, 6H); MS (APCI(+)) m/e 395 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:7][C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(I)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(I)ccc1OCc1ccccc1
Temperature: 120 °C

Procedure:
67.2 g (0.48 mol) of potassium carbonate are added to a solution of 100 g (0.40 mol) of 2-hydroxy-5-iodobenzaldehyde (Example 1A) in 1.5 l of dimethylformamide and, after a few minutes, 51 ml (0.44 mol) of benzyl chloride are added. The reaction mixture is stirred under reflux at 120° C. for 24 h. After stirring at RT for a further 24 h and the addition of 1.5 l of water, a solid crystallizes out. The precipitate is collected by suction filtration, washed twice with water and dried in vacuo. The solid is recrystallized from 230 ml of ethanol. 122.9 g (90% of theory) of product are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][NH:4][CH:3]1[CH2:8][OH:9].[C:10]([C@H:13]([C@@H:15]([C:17]([O-:19])=[O:18])[OH:16])[OH:14])([O-:12])=[O:11].C(O[C@H]1[C@H](OCC2C=CC=CC=2)[C@@H](COCC2C=CC=CC=2)NC1)C1C=CC=CC=1>C(O)(=O)C.CO.[Pd]>[OH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][NH:4][C@@H:3]1[CH2:8][OH:9].[C:10]([C@H:13]([C@@H:15]([C:17]([O-:19])=[O:18])[OH:16])[OH:14])([O-:12])=[O:11]
Reactant: OCC1NCC(O)C1O
Agent: [Pd]
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O

Procedure:
A more direct way to synthesise 3,4-dihydroxy-2-hydroxymethylpyrrolidine, D-tartrate is by reduring 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol with Pd/C in glacial acetic acid. The formed, oily (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-pyrrolidine,acetate is dissolved in methanol and added to a solution containing D-tartraric acid at reflux and (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine, D-tartrate is formed and can be isolated by filtration. Ion exchange chromatography is thereby avoided.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:16](Cl)(=[O:18])=[O:17])[C:8]=1[OH:20])=[O:4].[NH3:21]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:16](=[O:18])(=[O:17])[NH2:21])[C:8]=1[OH:20])=[O:4]
Reactant: O=C(CCl)NCc1cc2c(c(S(=O)(=O)Cl)c1O)CCC2
Reactant: N
Solvent: O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1c(O)c(CNC(=O)CCl)cc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
33.8 g (0.1 mole) of 6-(N-chloroacetylaminomethyl)-5-hydroxy-4-chlorosulfonylindane are dissolved in a little acetone, and the solution is added dropwise to 50 ml of concentrated ammonia solution. The mixture is stirred for 30 minutes at room temperature and is diluted with water. The precipitate which is deposited is filtered off with suction and dissolved in acetone, and the solution is filtered and stirred into water again.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:26]4[CH:27]=[CH:28][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([O:16][CH3:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:24][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 20.3 %

Procedure:
To a solution of [(S)-1-((2S,4S)-4-methoxy-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (100 mg, 0.19 mmol, Preparation 27) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.19 mmol) dissolved in toluene (1.18 mL) and water (0.43 mL) was added potassium carbonate (127 mg, 0.92 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2CH2Cl2 (13.55 mg, 0.017 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 90° C. overnight, cooled to RT, diluted with EtOAc and washed with water and brine to produce a dark colored solid, which was purified by silica gel chromatography (12 g silica, EtOAc/hexanes 40 to 100%) to produce the title intermediate (35.3 mg, 21% yield) as a yellowish colored solid. (m/z): [M+H]+ calcd for C44H52ClF3N8O8 913.35. found 913.3.