Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30]CC)=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:39])[N:3]=1.C1COCC1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:28]([OH:30])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:39])[N:3]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-(3-amino-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (60 mg), THF (1.5 mL), EtOH (absolute, 1 mL), and 2M aq NaOH (1 mL). The vessel was sealed and heated to 100° C. for 2 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C28H27ClN4O3S: 535.2, 537.2 (M+H+); Found: 535.2, 537.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.06 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.78-7.65 (m, 2H), 7.64-7.54 (m, 3H), 5.27 (s, 1H), 3.90 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.B(O)(O)O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Nc1ccccc1O
Agent: OB(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: c1c[nH]c(-c2nc3ccccc3o2)c1
Yield: 51.6 %

Procedure:
2-(Pyrrol-2-yl)benzoxazole was prepared as follows: A mixture of 5.55 g (0.05 mol) of pyrrole-2-carboxylic acid and 5.46 g (0.05 mol) of o-aminophenol and 3.09 g (0.05 mol) boric acid in 50 mL of xylene was heated under reflux for 3 days while removing water which was generated from reaction using a Dean-Stark trap. The cooled reaction mixture was diluted with 100 mL of ethyl acetate, washed with 150 mL of 5% sodium hydroxide solution and then with 150 mL of water. The separated organic layer was dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography on silica gel with 20% hexane in chloroform as eluant. The desired product, 2-(pyrrol-2-yl)benzoxazole (4.75 g, 52%), was obtained as a white solid. m.p. 149°-150° C.; 1H NMR (CDCl3) δ6.38-6.40 (m, 1H, ArH), 7.05-7.06 (m, 1H, ArH), 7.11-7.13 (m, 1H, ArH), 7.29-7.36 (m, 2H, 2xArH), 7.53-7.56 (m, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 10.9 (bs, 1H, NH).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxy-4-methylpentanoic acid (140 mg, 1.06 mmol) and HATU (403 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one (265 mg, 77%). LC/MS: m/z 421.30 (M+H)+ at 2.57 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J=8.3, 1.7 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H) 7.88 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.39 (m, 1H), 3.95 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.43 (m, 2H), 0.92 (q, J=3.8 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[N:14]=1.O>CN(C=O)C>[OH:19][C:15]1[N:14]=[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Nc1cccc(O)n1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(O)n1
Temperature: 85 °C
Yield: 29.5 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 1.5 g (12.8 mM) of 2-amino-6-hydroxypyridine in 25 ml of anhydrous DMF was heated at 85° C. for 5 hrs., cooled, and poured into 100 ml of water. The resulting precipitate was collected, washed successively with water, ethanol, ethyl acetate, and ether. Recrystallization from ethanol gave 1.0 g of the above urea as a yellow solid, m.p. 233°-234° C. (dec.).
Reaction SMILES: ClC(OCCCl)=O.[N:8]1([C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.[CH2:30]([NH2:33])[C:31]#[CH:32]>C(Cl)(Cl)Cl>[CH2:30]([NH:33][CH2:20][CH2:17][O:16][C:14]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:15])[C:31]#[CH:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCN
Agent: O=C(Cl)OCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNCCOC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-chloroethyl chloroformate (429 mg, 3 mmol) was added slowly to a mixture of tert-butyl 1-piperazinecarboxylate obtained as step (ii) in Example 2 (559 mg, 3 mmol) and diisopropylethylamine (407 mg, 3.15 mmol) in CHCl3 (25 ml) at 0° C. The mixture was stirred for 2 h at room temperature. CHCl3 (50 ml) was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was dissolved in CH2Cl2 (25 ml) at room temperature, and propargylamine (0.205 ml, 165 mg, 3 mmol) was added. After 24 h of stirring at room temperature, the solvent was removed by vacuum, and to the residue was added 20 ml of a solution of TFA:H2O:TES:thioanisole (85:5:5:5). The mixture was then stirred at room temperature for 2 h. The solution was evaporated to dryness in vacuum. The resulted residue was dissolved in water (10 ml) and then basified with Na2CO3 (pH 11), and extracted with Et2OAc (3×50 ml). The organic layer was washed with brine (2×50 ml) and dried over Na2SO4 overnight. Evaporation in vacuum gave the title compound H1: (251 mg, 40% total yield). H1 NMR (250 MHz, CDCl3+D2O) 2.26 (m, 1H), 3.11 (s 2H), 3.29 (dd, J=10.21, 7.45 Hz, 2H), 4.29 (d, J=11.23, 7.12 Hz, 2H), 2.55 (dd, J=4.73, 4.50 Hz, 4H), 2.93 (dd, J=4.96, 4.84 Hz, 4H). Mass spectrometry: calculated for C10HnN3O2 m/z [M+H]+=212.26. found [M+H]+=212.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:45][C:42]3[CH:43]=[CH:44][C:39]([N:36]4[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]4)=[CH:40][N:41]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A solution of 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (110 mg, 0.30 mmol) and 4-(6-amino-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester (310 mg, 1.1 mmol) in toluene was heated at 100° C. for 10 hours and then cooled to room temperature. Diethyl ether was added to the reaction mixture and the product precipitated. This precipitate was collected by filtration and dried to provide 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg, 29%). M++1: Calc'd. 578.3, Found 578.4.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.I[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: O=C1NCC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CC(c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Temperature: 100 °C

Procedure:
A reaction tube charged with 1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (20.0 mg, 0.0462 mmol), 4-iodoanisole (13.0 mg, 0.0554 mmol), K3PO4 (19.6 mg, 0.0924 mmol), and catalytic amount of CuI is purged with nitrogen. 1,4-Dioxane (0.5 mL) and catalytic amount of trans-1,2-diaminocyclohexane are added via syringe. The reaction mixture is heated at 100° C. overnight, cooled down to room temperature, quenched with saturated NH4Cl aqueous solution (5 mL), and extracted with EtOAc (3×3 mL). The combined organic layer is concentrated and purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C29H22ClF3N2O3 (M+H+) 539.1, found 539.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1.C(O)(=O)C.[H][H]>[Pd].O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: Clc1ccc(CC=C2CN3CCC2CC3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(CCC2CN3CCC2CC3)cc1

Procedure:
Combine 2.0 g (7 mmole) of 3-[2-(4-chlorophenyl)ethylidene]-1-azabicyclo[2.2.2]octane hydrochloride, 40 ml of acetic acid, 0.2 g of 10% Pd/C catalyst and 5 ml of water. Place the mixture in a Parr apparatus and hydrogenate the mixture at ca. 43 p.s.i. Follow the reaction by the uptake of hydrogen. When the theoretical amount of hydrogen has been absorbed stop the reaction. Remove the catalyst by filtration and wash the catalyst with 40 ml of acetic acid. Remove the solvent from the filtrate in vacuo. Recrystallize the residue from 2-propanol to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:24])[CH:20]=[CH:19][C:18]=1[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: CN(C)CCOc1cc(C(=O)O)ccc1-c1ccc(F)cc1
Reactant: Nc1ccc2cccnc2c1
Product: CN(C)CCOc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccc(F)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (20 mg, 0.14 mmol) and 2-(2-dimethylaminoethoxy)-4′-fluoro-1,1′-biphenyl-4-carboxylic acid (D79) (50 mg, 0.17 mmol) as a yellow solid. MS(ES): MH+ 430, M-H+ 428
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: Cn1ccc(C(N)c2nc3cc(Cl)ccc3[nH]2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(c2ccn(C)n2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine with TBTU and DIPEA in THF.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.CN1CCOCC1>CN1CCCC1=O>[CH:23]([C:21]1[CH:22]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:26]5[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]5)[CH:3]=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:18]=[N:19][CH:20]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Temperature: 120 °C

Procedure:
A mixture of 1-(6-fluoro-2-pyridyl)-6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridine (0.3032 mmol; 120.0 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.9095 mmol; 182.2 mg), and N-methylmorpholine (3.032 mmol; 310 mg; 0.337 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then partitioned between EtOAc and water. The organic layer was concentrated to afford tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate, which was used without purification.
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([OH:5])=O.CCN(CC)CC.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]2[O:37][N:36]=[C:35]([C@@H:38]3[CH2:42][CH2:41][CH2:40][NH:39]3)[CH:34]=2)[CH:26]=1.C(=O)(O)[O-].[Na+]>C1COCC1.ClC(OCC)=O>[F:17][C:2]([F:1])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:35]1[CH:34]=[C:33]([CH2:32][O:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[O:37][N:36]=1)=[O:5]
Reactant: c1cncc(OCc2cc([C@@H]3CCCN3)no2)c1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COc3cccnc3)on2)C1
Yield: 58.5 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetic acid (3.192 g) and Et3N (4.44 mL) in THF (100 mL), ethyl chloroformate (1.12 mL) was added at room temperature and the mixture was stirred for an hour. To the reaction mixture, a THF (50 mL) solution of the compound (2.607 g) obtained in Example 2-(3) was added dropwise at room temperature and the mixture was stirred at room temperature for 64 hours. To the reaction mixture, saturated aqueous sodium bicarbonate (200 mL) was added and the organic layer extracted with AcOEt (200 mL) was washed with brine (200 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by NH-form silica gel chromatography (AcOEt/hexane); the resulting compound was recrystallized (Et2O/pentane) to give the titled compound (2.969 g, colorless powder.)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[CH2:11]([O:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][CH:19]2[CH2:22][N:21]([C:23]3[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=3)[CH2:20]2)=[CH:16][CH:15]=1)[CH3:12]>C(Cl)Cl>[CH2:11]([O:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][CH:19]2[CH2:20][N:21]([C:23]3[CH:28]=[CH:27][C:26]([C@@H:29]([NH:31][C:7]([C:6]4[CH:5]=[C:4]([CH3:10])[O:3][C:2]=4[CH3:1])=[O:8])[CH3:30])=[CH:25][CH:24]=3)[CH2:22]2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Solvent: ClCCl
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)c4cc(C)oc4C)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 0.015 g (0.10 mmol) 2,5-dimethyl-furan-3-carbonyl chloride in 1 mL DCM is added a mixture of 0.031 g (0.10 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) and 0.010 g (0.10 mmol) TEA in 0.5 mL DCM. The mixture is stirred for 12 h at rt. The solvent is removed in vacuo and the residue is purified by HPLC to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[F:27][C:28]1[C:36]2[C:35](=[O:37])[O:34][C:33](=O)[C:32]=2[CH:31]=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[C:35](=[O:37])[N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[C:33]2=[O:34]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)c6cccc(F)c6C5=O)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 4-fluoro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:25]Br)[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]2)=[CH:14][CH:13]=1.[I-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH2:25][C:3]3[NH:2][CH:6]=[CH:5][N:4]=3)[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]2)=[CH:16][CH:17]=1
Reactant: c1c[nH]cn1
Reactant: CCC1COC(CBr)(c2ccc(Oc3cccc(Cl)c3)cc2)O1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1COC(Cc2ncc[nH]2)(c2ccc(Oc3cccc(Cl)c3)cc2)O1
Temperature: 25 °C

Procedure:
1.2 parts of imidazole sodium salt, 4 parts of 2-[p-(3chlorophenoxy)phenyl]-2-bromomethyl-4-ethyl-1,3-dioxolane and a catalytic amount of potassium iodide are stirred in 50 ml of dimethyl formamide for 17 hours at a temperature of 125° C. The brown reaction mixture is cooled to room temperature, diluted with 150 ml of water and extracted with three 50 ml portions of ethyl acetate. The combined extracts are washed with two 50 ml portions of water, and dried over sodium sulfate. The solvent is removed by evaporation and the crude product is chromatographed over a 35 cm column of silica gel with acetone/ethyl acetate (1:1). The eluant is removed by evaporation and the oily residue is crystallised from petroleum ether in the form of slightly yellowish crystals with a melting point of 69°-71° C.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>>[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C@@H:28]([OH:29])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14]
Reactant: C#CC(C)(C)C
Reactant: O=Cc1ccccc1Br
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@H](O)c1ccccc1Br
Yield: 76 %

Procedure:
The product was prepared by General procedure S using 50 mg (0.28 mmol) Cy2BH, 35 μL (0.28 mmol) 3,3-dimethyl-1-butyne, 0.26 mL (0.53 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, and 29 μL (0.25 mmol) o-bromobenzaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 76% yield (51 mg, 0.19 mmol). [α]D20=−31.8 (c=0.33, CHCl3, 93% ee); 1H NMR (CDCl3, 500 MHz): δ 1.02 (s, 9H), 2.03 (s, 1H), 5.46-5.53 (m, 2H), 5.86 (d, 1H, J=15.0 Hz), 7.13 (t, 1H, J=7.6 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.52 (d, 1H, J=8.9 Hz), and 7.54 (d, 1H, J=8.2 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 29.4, 33.0, 73.8, 122.6, 125.0, 127.7, 127.8, 128.9, 132.8, 142.3, and 144.3 ppm; IR (neat): 3353, 3064, 3013, 2958, 2865, 1721, 1661, 1590, 1568, 1465, 1439, 1363, and 1267 cm−1; HRMS-CI m/z 251.0432 [(M−OH)+; calcd for C13H16Br: 251.0435].
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].Cl[C:29]([O:31][CH3:32])=[O:30]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC)cc2)cc1)OCC
Reaction time: 144 h
Yield: 90.3 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (0.55 g; 1.4 mmole) was dissolved in tetrahydrofuran (5 ml) and methyl chloroformate (0.534 g; 5.68 mmole) was added slowly. The reaction mixture was continuously checked with HPLC and after 6 days was all the starting material consumed. Water was added to the mixture, tetrahydrofuran was evaporated and the residue extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated and 0.525 g (90.2%) of (S)-2-ethoxy-3-(4-[2-{4-(methoxycarbonylamino)phenyl}ethoxy]phenyl)propanoic acid ethyl ester was obtained.