Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:16])[C:12]([CH2:14][OH:15])=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[N:10]=[C:9]2[N:11]([CH3:16])[C:12]([CH2:14][O:15][C:18]3[CH:50]=[CH:49][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:24]4=[O:48])=[CH:20][CH:19]=3)=[N:13][C:8]2=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2nc(CO)n(C)c2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 85.8 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.33 g 5-isopropoxy-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 102), 0.69 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.37 ml of tributylphosphine, 0.38 g of 1,1'-(azodicarbonyl)di-piperidine and 20 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.85 g of the title compound, melting at 90°-100° C. (softening)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:53][CH:54]([C:57]1[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=1)[CH2:55][OH:56]>ClCCl>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:53][CH:54]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=3)[CH2:55][OH:56])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(CO)c1ccc(F)c(F)c1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 3.4 %

Procedure:
100 mg (0.31 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 111 mg (0.35 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 159 mg (1.57 mmol) of 4-methylmorpholine were initially charged in 2.0 ml of dichloromethane. After 10 min at RT, 142 mg (0.35 mmol) of 2-amino-2-(3,4-difluorophenyl)-ethanol were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and acetonitrile/methanol/water was added. A solid precipitated out, and this solid was filtered off and purified by chromatography on silica gel (mobile phase: dichloromethane:THF=10:1→5:1). The combined product fractions were concentrated and then triturated with acetonitrile, and the solid was filtered off and washed with methanol. This gave 39 mg of the target compound (26% of theory, purity 95%). After some time, the filtrate produced more solid; this gave another 5 mg of the target compound (3.3% of theory, purity 99%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CN(C)C=O.O>[CH2:1]([CH:3]([C:6]1[C:14]2[N:13]([CH2:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1cccc2c1n(CC(=O)OC(C)C)c(=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (23.2 g, 76.2 mmol) in N,N-dimethylformamide (120 mL) was added potassium carbonate (11.6 g, 83.9 mmol) and isopropyl bromoacetate (10.9 mL, 83.9 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude tert-butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](CF)=[CH:35][CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.[F:50][P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:50])=[CH:37][CH:38]=3)[CH2:20][N:21]3[C:22](=[O:31])[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]3=[O:30])=[O:16])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccc(CF)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (250 mg, 1.0 mmol), 2-{(2S)-2-amino-3-[4-(fluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (313 mg, 1.05 mmol) [prepared according to the procedure of Preparation 6] and diisopropylethylamine (0.52 ml, 3 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (746 mg, 1.6 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding the title compound as a yellow solid (490 mg, 0.92 mmol, 92% yield) as a yellow foam: LCMS (ES) m/e 531 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]1[CH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[C:20]=2[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH3:58][NH2:59].Cl>C(Cl)Cl.O>[CH3:58][NH:59][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH2:19][CH2:18][CH:17]2[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:16])[C:2]1=[O:1])=[O:27]
Reactant: CN
Reactant: O=C(O)c1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cccc2c1CCC2n1cccc(C(=O)Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 1-(2-oxo-3-(pyridin-4-ylcarbamoyl)pyridin-1(2H)-yl)-2,3-dihydro-1H-indene-4-carboxylic acid (45 mg, 1.0 eq) in DCM (4 mL) was added EDC.HCl (1.5 eq), HOBt (1.5 eq), Et3N (3.0 eq) and MeNH2.HCl (1.1 eq) The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM. The combined organic layer was washed with brine and dried over MgSO4, evaporated the filtrate to give the crude product, which was purified by HPLC to afford 1-(4-(methylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (18 mg, 39%). 389.2 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.73 (d, J=3.6 Hz, 2H), 8.51 (dd, J=1.2 Hz, 4.2 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H), 8.20 (d, J=3.6 Hz, 2H), 7.74 (d, J=4.2 Hz, 1H), 7.60 (d, J=4.2 Hz, 1H), 7.35 (t, J=4.2 Hz, 1H), 7.27 (d, J=4.2 Hz, 2H), 6.65 (t, J=4.2 Hz, 1H), 6.55 (t, J=4.2 Hz, 1H), 3.37 (overlap with DMSO-d6, 2H), 2.60-2.75 (m, 1H), 2.05-2.15 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[NH:21]1[CH2:25][CH2:24][C@@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:21]3[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: N[C@@H]1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)C1
Temperature: 60 °C
Yield: 57.4 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (700 mg, 2.65 mmol) obtained in Step 6 of Example 1, tert-butyl (R)-(pyrrolidin-3-yl)carbamate (740 mg, 3.98 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (710 mg, 3.72 mmol) and N-methylmorpholine (0.608 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (1.5 mL), and the solution was added with a 4 mol/L solution of hydrogen chloride in methanol (1.50 mL), followed by heating under reflux at 60° C. for 60 minutes. The reaction mixture was concentrated under reduced pressure, the residue was added with saturated aqueous potassium carbonate solution and ethyl acetate and was extracted. The crude product was crystallized from ethyl acetate to obtain Compound 158 (506 mg, 58%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([C:26](O)=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:33]1([NH:35][C:26]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:27])[CH2:34][CH2:32]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 188.6 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(3-phenylpropyl)-1H-1,2,3-triazole-4-carboxylic acid (398 mg, 1.05 mmol) obtained in Example 100b), HOBt (71.8 mg, 0.526 mmol, 0.5 eq.) and cyclopropylamine (0.098 ml, 1.37 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 6 ml), WSC (247 mg, 1.26 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr. Water (20 ml) was added to the reaction mixture, and the mixture was stirred. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (414 mg, 0.992 mmol, 94.4%).
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][O:12][CH3:13])[O:10][C:6]=2[C:5]([NH2:14])=[CH:4][C:3]=1[CH3:15].[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][CH2:11][CH:9]1[CH2:8][C:7]2[C:2]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[C:3]([CH3:15])[CH:4]=[C:5]([NH2:14])[C:6]=2[O:10]1
Reactant: COCC1Cc2c(Br)c(C)cc(N)c2O1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1Cc2c(c(N)cc(C)c2-c2ccncc2)O1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-2-(methoxymethyl)-5-methyl-2,3-dihydrobenzofuran-7-amine (8c) (0.85 g, 3.1 mmol), pyridin-4-ylboronic acid (0.76 g, 6.2 mmol), Cs2CO3 (2.5 g, 7.8 mmol), Pd(PPh3)4 (0.18 g, 0.16 mmol) and water (6 mL) in DMF (20 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (60 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (8d) as a yellow oil. MS-ESI (m/z): 271 (M+1)+.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH:15]([CH3:18])[CH2:16][CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 87 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 16, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N,-diisopropylethylamine (0.408 mL, 2.34 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.337 g, 1.17 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.536 g (87%) of the pure titled compound as a white foam: mp 64-77° C. APCI-MS m/z 527.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.Cl>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C#N)c1cccc(O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1Oc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 2-(3-hydroxyphenyl)propionitrile (0.118 g, 0.80 mmol), prepared as above described, in dry CH2Cl2 (6 mL were sequentially added, molecular sieves (4 Å), CuOAc (0.145 mg, 0.80 mmol) and pyridine (0.33 mL, 4.0 mmol). After stirring 20 min commercial 2-methoxyphenylboronic acid (0.243 g 1.60 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0° C., 0.5N HCl added and the organic phase washed (3×10 mL) with 0.5N HCl. After drying over Na2SO4 and solvent evaporation under reduced pressure a residue was obtained that, after flash chromatography (eluent mixture n-hexane/EtOAc 9:1), afforded 2-{3-[(2-methoxy)phenoxy)phenyl]propionitrile as pale yellow oil (0.172 g, 0.68 mmol). Yield 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.09, m/z=450; 1H NMR (CDCl3) 1.26-1.39 (m, 1H), 1.50 (d, 3H), 1.59-1.70 (m, 1H), 1.81-1.99 (m, 3H), 2.09-2.20 (m, 2H), 2.22-2.34 (m, 1H), 2.71 (s, 3H), 2.90 (m, 1H), 3.50 (t, 2H), 5.67 (m, 1H), 6.90-7.08 (m, 4H), 7.19 (m, 1H), 7.21 (m, 1H), 7.33 (d, 1H), 7.62 (d, 1H), 7.77 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]1([C@H:47]([NH:49][C:50]([NH2:52])=[O:51])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1.C(Cl)Cl>[CH3:34][O:33][C:11]1[C:5]2[C:6]([CH2:8][O:9][CH3:10])=[N:7][C:2]([NH:52][C:50]([NH:49][C@@H:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:48])=[O:51])=[CH:3][C:4]=2[NH:13][N:12]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COCc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(OC)c12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
BrettPhos pre-catalyst (6.80 mg, 8.51 μmol), 6-chloro-3-methoxy-4-(methoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (40 mg, 0.085 mmol), cesium carbonate (83 mg, 0.255 mmol), and (R)-1-(1-phenylethyl)urea (20.96 mg, 0.128 mmol) were taken up in dioxane (1 mL) in a 1.5 mL microwave vial and the vial was evacuated and back-filled with N2 (×3). The reaction mixture was stirred at 90° C. for 2 h. The crude reaction mixture was diluted with DCM, filtered through a syringe filter, and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 mL), charged with triethylsilane (100 uL), and stirred at room temperature for 10 min. The reaction mixture was concentrated in vacuo and the residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS—HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-methoxy-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C18H21N5O3 [M+1]+ 356. found 356. 1H NMR (500 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 7.25 (m, 4H), 6.86 (s, 1H), 5.02 (br s, 2H), 5.01-4.98 (m, 1H), 4.10 (s, 3H), 3.58 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH:15][C:25](=[O:26])[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH3:28])[CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(F)ccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)ccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-fluoro-N1-phenylbenzene-1,2-diamine (866 mg, 4.3 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (890 mg, 4.7 mmol), HOAt (640 mg, 4.7 mmol), 4-methylmorpholine (1.0 mL, 9.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (900 mg, 4.7 mmol) in DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (MgSO4) and concentrated in vacuo affording (S)-tert-butyl 1-(5-fluoro-2-(phenylamino)phenylamino)-1-oxopropan-2-ylcarbamate as a yellow-orange solid (quantitative), used in the following step without further purification. LCMS: RT 3.83 min [M+H]+ 374.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:28])([F:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:28])([F:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)C(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(F)(F)c1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionate (5.88 g, 13.8 mmol) in tetrahydrofuran-ethanol (30 ml—30 ml) was added 1N sodium hydroxide (28 ml, 28 mmol) at room temperature, and the mixture was stirred overnight at room temperature. After completion of the reaction, the organic solvent was evaporated under reduced pressure. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionic acid (4.24 g, 77%) as colorless crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[S:24][C:20]=2[CH:19]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:28]3[CH2:29][CH2:30][N:25]([C:23]4[S:24][C:20]5[CH:19]=[C:18]([Cl:17])[CH:32]=[CH:31][C:21]=5[N:22]=4)[CH2:26][CH2:27]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCN(c3nc4ccc(Cl)cc4s3)CC2)C1
Yield: 10.9 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.2 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.2 g of 1-(6-chlorobenzothiazol-2-yl)piperazine to give 0.04 g of 6-acetyl-3-(2-(4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 180° C. (decomposition) as an oxalate thereof.