Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[C:28]=1[Cl:34].Cl.CCO>>[Cl:26][C:27]1[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=1[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-3-methylbutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (940 μL, 12 mmol). Sodium hydride (5.6 mg, 233 μmol) was then slowly added, and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluoro-benzene (64.1 mg, 388 μmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated under vacuum. 1.2M HCl in EtOH (1.1 mL, 1.3 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (37.4 mg, 100% purity). MS m/z: [M+H] calcd for C15H21Cl2NO, 302.10. found 302.2.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([C@@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[C:7]([OH:16])[CH:6]=1.[CH3:17]O>>[CH3:17][O:13][C:12](=[O:14])[CH:11]([NH2:15])[C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][CH:5]=1
Reactant: CO
Reactant: N[C@@H](C(=O)O)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mL of methanol cooled to 0° C. was dropwise added 3.75 mL of thionyl chloride foolowed by 5.0 g (0.030 mmol) of D-4-hydroxyphenylglycine. The reaction was heated to reflux for 5 h then stirred overnight at room temperature. The resulting mixture was concentrated in vacuo and the residue was diluted with ether. The resulting solid was collected by filtration and dried in vacuo to provide 5.9 g of amino-(4-hydroxy-phenyl)-acetic acid methyl ester as a white solid. Electrospray Mass Spec 182.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=2)[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:27])[CH2:16][C:15]1([CH3:35])[CH3:34])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:25])=[CH:21][CH:22]=2)[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([CH3:27])[CH2:16][C:15]1([CH3:35])[CH3:34])(=[O:13])[CH3:12]
Reactant: COc1ccc(CO)cc1
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)c2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 4-methoxybenzylalcohol (6.2 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:32]([O:39][C:40](=[O:41])[N:11]([CH2:10][CH:9]([OH:16])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:14])[CH3:15])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -1.5 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester (2) (24.50 g, 72.80 mmol, 1 equiv) and triethylamine (7.37 g, 72.80 mmol, 1 equiv) were dissolved in dichloromethane (500 mL). The solution was cooled to −1.5° C., followed by the dropwise addition of benzylchloroformate (12.40 g, 72.80 mmol, 1 equiv). The solution was stirred at 0° C. for 24 h. Due to the incompleteness of the reaction, benzylchloroformate (2.40 g, 14.07 mmol) and triethylamine (1.44 g, 14.23 mmol) were added to the solution. The solution was stirred at room temperature for 24 h. The solution was diluted with 2% Na2CO3 solution (300 mL) and the mixture was stirred for 10 min. The organic layer was separated, washed with water (2x) and saturated sodium chloride solution (1×). The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a yellow colored oil (34.30 g, 72.80 mmol, quantitative). LRMS (ES+): m/z 471 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=2)([O:17][CH3:32])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:19][CH:20]=1
Reactant: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C(C)n1cncn1
Reaction time: 2 h

Procedure:
1,1-Bis-(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazolyl)propan-1-ol (0.5 g) was added portionwise over a period of 15 minutes to a suspension of sodium hydride (58 mg, freed from dispersion in oil by washing with hexane) in dry dimethylformamide (50 cm3) under a nitrogen atmosphere. The mixture was stirred for 2 hours then methyliodide (0.17 g) in dimethylformamide (2 cm3) was added dropwise. After stirring for 3 hours the mixture was partitioned between water and chloroform. The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent to yield 1,1-bis(4-trifluoromethylphenyl)-1-methoxy-2-(1,2,4-1H-triazolyl)propane as a colourless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:15][CH:14]=[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9][C:4]2=[C:3]1[C:16]#[N:17].IC.[C:20](=O)([O-])[O-].[K+].[K+]>O>[CH3:20][N:15]1[C:2](=[O:1])[C:3]([C:16]#[N:17])=[C:4]2[C:5]([S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9]2)=[CH:14]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccccc1N2
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1cc2c(c(C#N)c1=O)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 24 parts of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile, 14 parts of iodomethane and 14 parts of potassium carbonate is stirred at room temperature for 21/4 hours, then diluted with 2 volumes of water. The precipitate which forms is filtered out, dried in vacuo, and recrystallized from acetonitrile to give yellow needles of 2,3-dihydro-2-methyl-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile melting at 292°-295° with decomposition.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Reactant: C1COCCN1
Agent: Cl
Product: O=C(NOCc1cccc(C(=O)N2CCOCC2)c1)c1ccccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and morpholine hydrochloride. 1H-NMR (DMSO-d6) δ 11.6 (bs, 1H), 8.49 (m, 2H), 7.89 (bt, 1H), 7.56 (m, 1H), 7.52-7.44 (m, 2H), 7.42-7.34 (m, 2H), 7.31 (m, 2H), 7.19 (m, 1H), 6.58-6.49 (m, 2H), 4.98 (s, 2H), 4.47 (d, 2H), 3.80-3.10 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1.FC(F)(F)COC1C2C(OCCC3CCN(CC4(C(OC)=O)CCOCC4)CC3)=NOC=2C=CC=1>>[CH:28]1([CH2:27][O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: BrCC1CCC1
Agent: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4CCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 7 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, Step 2) and (bromomethyl)cyclobutane instead of methyl 4-[(4-{2-[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]ethyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate (Step 7 of EXAMPLE 7).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1
Reactant: N#CC1CNC1
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC1CN(CCCCl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
In a 25 mL round-bottomed flask were mixed with stirring azetidine-3-carbonitrile hydrochloride (available from ASW MedChem. Inc., 250 mg, 2.11 mmol) and 1-bromo-3-chloropropane (664 mg, 415 μL, 4.22 mmol.0) in acetonitrile (5 mL) to the suspension was added Cs2CO3 (2.06 g, 6.33 mmol). The mixture was stirred at 25° C. for 18 h, then diluted with 15 mL of EtOAc and filtered to remove solids. Filtrate was evaporated and residue purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane (developing TLC in an iodine chamber) to give 1-(3-chloropropyl)azetidine-3-carbonitrile (230 mg, 1.45 mmol, 68.8%) as a clear dense liquid. 1H NMR (CDCl3) δ: 3.46-3.59 (m, 4H), 3.20-3.31 (m, 3H), 2.55 (t, J=6.8 Hz, 2H), 1.75 (quin, J=6.6 Hz, 2H).
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([C:20](Cl)=[O:21])=[CH:17][C:16]=2[CH:23]=1.[CH2:24]([NH:31][CH3:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[CH2:24]([N:31]([CH3:32])[C:20]([C:18]1[O:19][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:3]3[S:2][C:10]4[C:5]([N:4]=3)=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:23][C:16]=2[CH:17]=1)=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Yield: 15.1 %

Procedure:
To a solution of 5-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carbonyl chloride hydrochloride (150 mg, 0.43 mmol) in CH2Cl2 (4.3 mL) was added N-benzyl-N-methylamine (55 μL, 0.43 mmol) and Et3N (0.12 mL, 0.86 mmol). The reaction mixture was stirred (rt, 2 h) before additional N-benzyl-N-methylamine (55 μL, 0.43 mmol) was added. The mixture was concentrated and purified by reverse phase chromatography to provide the title product as an orange oil (27 mg, 15%). MS (ESI): mass calcd. for C23H17N3O3S, 415.10; m/z found, 416.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.60 (d, J=3.7, 1H), 8.09 (dd, J=7.9, 1.5, 1H), 7.75 (br s, 1H), 7.66-7.49 (m, 1H), 7.46-7.28 (m, 8H), 5.05-4.62 (m, 2H), 3.45-2.94 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:3]=[C:4]([NH2:11])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Nc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Nc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]ccc12
Temperature: 115 °C
Yield: 12.8 %

Procedure:
To a mixture of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.06 g, 0.353 mmol) in nBuOH (0.7 mL) was added 6-aminoindazole (0.094 g, 0.70 mmol) and TMSCl (0.023 mL, 0.175 mmol). After heating at 115° C. for 8 h, it was cooled and purified by prep HPLC to give N2-(1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (0.012 g, MS calcd for C13H11N7 265.3. found 266.1; UV 216.9, 308.0 nm).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[O:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)Cl>[C:9]([O:8][C:6](=[O:5])[NH:4][CH2:1][C:2]#[CH:3])([CH3:12])([CH3:11])[CH3:10]
Reactant: C#CCN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C#CCNC(=O)OC(C)(C)C

Procedure:
A solution of propargylamine (1 g, 18 mmol) in DCM (10 mL) was treated with (BOC)2O (4.0 g, 18 mmol) at rt for 3 h. Evaporation gave the title compound as an oil. 1H NMR (CDCl3) δ 4.80 (s, 1H), 3.93 (s, 2H), 2.23 (t, 1H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCSc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 4-bromobenzenethiol (10.1 g), and to the solution was added at room temperature potassium carbonate (9.6 g). To the mixture was added dropwise 1-iodohexane (9.5 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 1-bromo-4-(hexylthio)benzene (14.2 g). In THF (127 ml) was dissolved 1-bromo-4-(hexylthio)benzene (14.1 g), and to the solution was added dropwise at −78° C. 1.6M n-butyllithium/hexane (35.5 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (16.1 g) in THF (32 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (70.5 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(hexylthio)phenyl borate (6.6 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][C:22]=2[CH3:28])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(F)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-fluorophenylboronic acid as starting materials in step D. MS (ES): 476.2 [M−H]−.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1.[Cl-].[Na+].O>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl indane-2-carboxylate (Schaaf et al., J. Med. Chem. 1983, 26, 328-334) (2.00 g, 10.5 mmol) in THF at −78° C. was added sodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF, 15.8 mmol) dropwise, over 10 min. The mixture was stirred for 15 min, then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added dropwise, over 30 min. The resulting mixture was stirred for 30 min at −78° C., then poured into brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=368 (M+Na+CH3CN).
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22]([C@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[C@H:25]1[NH2:35])[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:35][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=3)[CH2:32][C@@H:24]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CC[C@H]1Cc2ccc(OC)cc2[C@H]1N
Product: CCc1cnc(CC)c(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 0.93, 1.27–1.34, 2.58, 2.68, 3.00, 3.79, 4.44, 5.83, 6.80, 6.92, 7.17, 7.68; HRMS (EI) calcd for C20H27N3O 325.2154, found 325.2157.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH:11]1([CH2:17]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O>CO>[CH:11]1([CH2:17][O:10][C:9]2[C:4]([NH2:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrCC1CCCCC1
Reactant: Nc1ncccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ncccc1OCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At RT, 96 g of sodium hydroxide (45%; 1081 mmol, 1 equivalents) were initially charged in 1170 ml of methanol, 119 g of 2-amino-3-hydroxypyridine (1080 mmol, 1 equivalent) were added and the mixture was stirred at RT for 10 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2900 ml of DMSO and 101 g of cyclohexylmethyl bromide (1135 mmol, 1.05 equivalents) were added. After 16 h at RT, the reaction mixture was stirred into 6 l of water, and the aqueous solution was extracted twice, in each case with 2 l of ethyl acetate. The combined organic phases were washed with in each case 1 l of saturated aqueous sodium bicarbonate solution and water, dried, filtered and concentrated. The residue was stirred with 500 ml of pentane, filtered off and dried under reduced pressure. This gave 130 g (58.3% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=CN=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)C.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:8][O:10][C:11](=[O:14])[CH2:12][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:1]1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C[C@@H]1CCCO1
Temperature: 25 °C

Procedure:
A mixture of crude hydroxy-pyridine 22b (30.0 g, 0.151 mol), bromo-acetic acid ethyl ester (16.9 ml, 0.151 mol) and K2CO3 (41.7 g, 0.301 mol) in acetone (1000 mL) is heated to reflux for 5 h. The mixture is cooled to RT, poured into water (800 mL) and extracted with EtOAc (500 mL×2). The combined organic layers are washed with brine, dried (Na2SO4). The solvent is evaporated and the residue is purified by column to afford ester 22c.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 79 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.887 g, 5.16 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride then was removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a precipitate. The solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.741 g, 1.94 mmol, 49%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:29]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>ClCCl>[NH2:47][C:9]1[C:8]2[N:29]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
tert-Butyl 2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (2.8 g, 5.05 mmol) was dissolved in dichloromethane (35 mL) and ammonium hydroxide (25 mL). p-Toluenesulfonyl chloride (0.962 g, 5.05 mmol) was added in one portion and the reaction was stirred for 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organics were combined and evaporated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (silica gel, 2-25% CMA in chloroform) to provide 1.95 g of tert-butyl 2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as white crystals.