Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9](/[CH:30]=[CH:31]/[C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])[CH:10]=[C:11]([CH3:29])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:16][N:15]=1.[CH:40]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1)=[CH2:41].C([O-])([O-])=O.[K+].[K+]>O>[Cl:6][C:7]1[CH:8]=[C:9](/[CH:30]=[CH:31]/[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:46][C:45]3[CH:48]=[CH:49][C:42]([CH:40]=[CH2:41])=[CH:43][CH:44]=3)[CH2:36][CH2:35]2)=[O:33])[CH:10]=[C:11]([CH3:29])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:16][N:15]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: Cc1cc(/C=C/C(=O)N2CCNCC2)cc(Cl)c1Oc1ccc(OCc2ccccc2Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(CN2CCN(C(=O)/C=C/c3cc(C)c(Oc4ccc(OCc5ccccc5Cl)cn4)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a DMF (7 mL) solution of (E)-3-[3-chloro-4-({5-[(2-chlorobenzyl)oxy]-pyridin-2-yl}oxy)-5-methylphenyl]-1-(piperazin-1-yl)prop-2-en-1-one (0.70 g) and 4-vinylbenzyl chloride (240 μL) was added K2CO3 (291 mg) at room temperature. After stirring at room temperature for 36 hours, to the reaction mixture was added water, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 0/1 and then AcOEt/MeOH=19/1) to give (E)-3-[3-chloro-4-({5-[(2-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-[4-(4-ethenylbenzyl)-piperazin-1-yl]prop-2-en-1-one as a colorless powder (0.73 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C1([Mg]Br)C=CC=CC=1.[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[OH:8]
Reactant: Oc1c(Br)cncc1Br
Reactant: O=Cc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1c(Br)cncc1C(O)c1ccccc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a heterogeneous mixture of 3,5-dibromo-4-hydroxypyridine (2.53 g, 10 mmol, prepared following the procedure in Synthesis, 2001, 14, 2175-2179) in anhydrous THF (20 mL) at −78° C. under Ar-atm was added phenylmagnesium bromide solution (11 mL of 1 M solution in THF, 11 mmol). After stirring for 15 min. was added n-BuLi solution (5.5 mL of 2 M solution in cyclohexane), and the reaction mixture was stirred for 15 min at −78° C. under Ar-atm. To this mixture benzaldehyde (2.15 mL) was added and the reaction mixture was stirred for 2 h −78° C. under Ar-atm. The reaction mixture was quenched by adding HOAc (3 mL) and TFA (3 mL), concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc/MeOH/750:250:50 followed by hexane/EtOAc/MeOH/Et3N/460:460:50:10 to afford the desired product (2.85 g, 91%) as a white solid. 1H NMR (CD3OD) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.41-7.20 (m, 5H), 5.94 (s, 1H); MS (ESI+) m/z 280, 282 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1.Cl>C(O)(C)C>[CH3:23][N:24]1[CH:28]=[C:27]([NH:29][C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=[CH:10][C:5]3=[CH:4][N:3]=2)[CH:26]=[N:25]1
Reactant: CS(=O)(=O)Nc1ccccc1Cn1ncc2cnc(Cl)nc21
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4NS(C)(=O)=O)c3n2)cn1
Temperature: 140 °C

Procedure:
A suspension of N-(2-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanesulfonamide (53 mg, 0.16 mmol), 1-methyl-1H-pyrazol-4-amine (0.24 mmol) and HCl (0.26 mmol, 4M in dioxane) in isopropanol was heated in the microwave at 140° C. for 1 h. After cooling to rt the mixture was washed with H2O, extracted with DCM then dried using a hydrophobic frit. The organic phase was concentrated in vacuo. Purification was performed by prep. HPLC. The desired fractions were concentrated in vacuo to afford the title compound. 1H NMR (d6-DMSO) δ 9.88 (s, 1H), 9.44 (s, 1H), 8.94 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.13 (t, 1H), 6.71 (s, 1H), 5.71 (s, 2H), 3.79 (s, 3H), 3.06 (s, 3H); LC-MS method B, (ES+) 399, RT=7.14 min
Reaction SMILES: C(O[CH2:5][C:6]1[NH:7][C:8]([C:15](=[O:17])[CH3:16])=[C:9]([CH3:14])[C:10]=1[C:11](=O)[CH3:12])(=O)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>ClC(Cl)C>[C:15]([C:8]1[C:9]([CH3:14])=[C:10]2[C:6]([N:7]=1)=[CH:5][C:20]1[C:19]([N:18]=[C:26]3[C:21]=1[CH:22]=[CH:23][CH:24]=[CH:25]3)=[C:11]2[CH3:12])(=[O:17])[CH3:16]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)OCc1[nH]c(C(C)=O)c(C)c1C(C)=O
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(=O)C1=Nc2cc3c(c(C)c2=C1C)N=c1ccccc1=3
Yield: 34.9 %

Procedure:
To a solution of 2-acetoxymethyl-3,5-diacetyl-4-methylpyrrole (0.200 g) and indole (0.098 g) in dichloroethane (90 cm3) was added Montmorillonite K10 clay (0.30 g). The mixture was stirred and heated at reflux for 80 h. After cooling the clay was removed by filtration and the filtrate concentrated to ca 20 cm3 in vacuo. The crude product was removed by filtration and then chromatographed on silica. Elution with chloroform-methanol (60:1) yielded 0.08 g of the title compound as a yellow solid m.p. 258°-260° C., m/z (EI) 276 (M+) δH ([2H6 ]-DMSO) 2.58 (3H, s, COCH3), 2.88 (3H, s, CH3), 2.92 (3H, s, CH3), 7.05 (1H, m, 8-H), 7.38 (2H, m, 6-H, 7-H), 7.85 (1H, s, 10-H), 8.08(1H, J, 8 Hz, 9-H), 10.6 (1H, s, NH), 11.17 (1H, s, NH). (Found: C, 77.0; H, 5.74; N, 9.76; C18H16N2 O. 0.14 EtOAc requires C, 77.2; H, 5.98; N, 9.70%.)
Reaction SMILES: CN(C)[N:3]=[CH:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1.Cl[C:13](=[CH2:16])[C:14]#[N:15].C(N(CC)CC)C>O1CCOCC1>[C:14]([C:13]1[N:3]=[CH:4][C:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:16]=1)#[N:15]
Reactant: C=C(Cl)C#N
Reactant: CN(C)N=CC1=CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(cn1)CCCC2

Procedure:
7.6 g cyclohex-1-ene-carboxaldehyde-N,N-dimethylhydrazone, 4.4 g of 2-chloroacrylonitrile and 10.1 g of triethylamine are heated in 75 ml of dioxane for 18 hours to 90° C. The reaction mixture is concentrated by evaporation and the residue is acidified with 1N HCl and extracted three times with chloroform. The combined extracts are dried and concentrated by evaporation and the residue is chromatographed over silica gel. Pale yellow crystals of the title compound are isolated. Melting point: 56°-59° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([OH:74])[CH2:56][N:57]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=2[F:73])=[CH:62][CH:61]=1)[NH2:58])[CH3:52]>>[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([OH:74])[CH2:56][N:57]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=2[F:73])=[CH:64][CH:65]=1)[NH:58][C:9]([C:7]1[NH:6][N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:8]=1)=[O:11])[CH3:52]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (168 mg, 1.1 mmol) and HCTU (451 mg, 1.1 mmol) were combined in DMF (6.8 mL, 87.2 mmol), and stirred at room temperature. After 15 minutes, DIPEA (570 μL, 3.3 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (400 mg, 1.1 mmol) were added. The mixture was stirred for 20 minutes at room temperature, then evaporated under reduced pressure to yield the title compound. MS m/z [M+H]+ calc'd for C24H24ClFN4O5, 503.14. found 503.2.
Reaction SMILES: [F:1]C(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40](C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:37]1[CH:38]=[CH:39][C:34]([CH2:40][N:24]2[CH2:25][C@@H:26]3[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]3[CH2:23]2)=[CH:35][CH:36]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccc(F)cc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 4-fluorobenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61 (t, J=7.2, 1H), 7.64 (dd, J=2.4, 7.5, 2H), 7.39 (dd, J=5.8, 8.2, 1H), 7.33 (dt, J=5.8, 11.6, 3H), 7.28-7.23 (m, 1H), 7.11 (dd, J=8.8, 19.1, 2H), 4.34 (dd, J=5.8, 12.6, 1H), 3.56 (d, J=13.3, 0.5H), 3.45 (dd, J=13.3, 16.8, 1H), 3.31 (d, J=13.1, 0.5H), 3.22 (dd, J=2.3, 10.5, 1H), 2.92 (d, J=6.5, 0.5H), 2.69-2.60 (m, 1H), 2.57 (d, J=6.6, 1H), 2.51 (d, J=8.4, 1H), 2.46-2.33 (m, 1H), 2.29 (d, J=4.4, 1H), 2.22 (d, J=6.5, 1H), 2.14 (dq, J=6.2, 12.2, 0.5H), 1.95-1.80 (m, J=7.1, 12.4, 20.7, 1H), 1.79-1.72 (m, 0.5H), 1.71-1.64 (m, 1H), 1.48-1.23 (m, 1.5H), 1.20 (t, J=6.1, 3H), 0.70 (dd, J=2.1, 6.7, 3H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:11][C@@H:10]2[CH3:26])=[O:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([N:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[C:38](=[O:40])[CH3:39])[CH2:11][C@@H:10]2[CH3:26])=[O:8])=[CH:27][CH:28]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccncc3)C[C@@H]2C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccncc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-N-pyridin-4-yl-1,2,3,4-tetrahydroquinolin-4-amine (90 mg, 0.24 mmol, 1 equ.) in methylene chloride (0.8 mL) was added diisopropylethylamine (84 uL, 0.48 mmol, 2 equ.) followed by acetyl chloride (340 uL, 4.80 mmol, 20 equ.). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride/methanol 97/3) to afford pure N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-pyridin-4-ylacetamide (60 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[N:18]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[O:11][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ccncc3o2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cccc(-c2nc3ccncc3o2)c1
Yield: 31.2 %

Procedure:
A suspension of 2-(3-nitrophenyl)oxazolo[5,4-c]pyridine (1.20 g, 5 mmol), iron powder (1.40 g, 25 mmol) and NH4Cl (2.14 g, 40 mmol) in CH3OH:H2O (4:1, 60 mL) was refluxed for 6 hrs. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was poured into water. The precipitate was collected by filtration, and washed with water (20 mL×3) to afford 3-(oxazolo[5,4-c]pyridin-2-yl)benzenamine as a white solid (0.330 g, yield: 31%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:27]5[S:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(C(F)(F)F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.26 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc-EtOH to give the title compound (55.7 mg) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[O:29][C:28]([CH3:30])=[N:27][C:26]=3[CH3:31])=[O:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[O:29][C:28]([CH3:30])=[N:27][C:26]=3[CH3:31])([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3oc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.58 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (200 mg, 2.41 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (20 mL) and the colorless solution was cooled to −40° C. Then, n-BuLi (2.5 M in hexanes, 1.0 mL, 2.5 mmol) was added drop wise which afforded a dark reddish-brown viscous solution. The mixture was stirred at −30° C. for 35 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanone (500 mg, 1.05 mmol, in 4 mL THF, Intermediate 87: step b) was introduced at −20° C. The reaction mixture became a dark brown color and was then placed in an ice-water bath and allowed to warm gradually to room temperature. After 45 minutes, the mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc:THF (10:2), 4×50 mL. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (3% MeOH-DCM increasing to 5% MeOH-DCM) to provide the title compound as a faint amber solid. MS m/e 558.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.54-7.47 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 4.35 (s, 2H), 4.10 (s, 3H), 4.03 (s, 1H), 3.92 (s, 3H), 2.40 (s, 3H), 1.54 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
A solution of methyl 2-(4-bromophenyl)-2,2-dimethylacetate (3880 μL, 15090 μmol) in EtOH (80 mL) and water (20 mL) was treated with KOH (4233 mg, 75450 μmol). The reaction was heated to 90° C. After 15 hours, the reaction was cooled to 23° C. and concentrated in vacuo. The crude mixture was partitioned between water/diethyl ether (150 mL each). The aqueous layer was separated and extracted with diethyl ether (100 mL). The combined ether layers were then extracted with a 1N NaOH solution (25 mL). The combined aqueous washes were acidified with concentrated HCl to pH=2.0 and extracted with EtOAc (3×100 mL). The combined EtOAc layers were dried over MgSO4, and concentrated in vacuo to afford 3144 mg of 2-(4-bromophenyl)-2-methylpropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10](C(O)=O)[N:9]=2)[CH:5]=[N:6][CH:7]=1.C1(P([N:54]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:16][C:12]=3[CH:11]=[C:10]([NH2:54])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)O)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Example 3.22, prepared from Example 2.1, Step 4 using a procedure similar to that described for Example 1.1, Step 5; 500 mg, 0.91 mmol) in DMF (6 mL) was added TEA (0.2 mL, 1.83 mmol), and the reaction was deoxygenated by purging with nitrogen for 5 minutes. To this reaction mixture was added diphenyl phosphoryl azide (0.4 mL, 1.83 mmol) and the reaction flask was sealed. The mixture was stirred at rt for 1 h and then H2O (2 mL) was added. Again, the reaction flask was sealed and the reaction was heated at 90° C. for 1.5 h. The reaction was then diluted with water and EtOAc. The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (2% MeOH/CH2Cl2) to yield 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-amine. MS ES/APCl calc'd. for C29H33ClN6O [M+H]+ 517. found 517.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.[C:12]([OH:16])(=O)[CH:13]=O.O.[NH2:18][NH2:19]>C(O)(=O)C>[N:18]1[NH:19][C:12](=[O:16])[CH:13]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]=12
Reactant: O=C1CCc2ccccc21
Reactant: NN
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc2c(n[nH]1)-c1ccccc1C2

Procedure:
By a method similar to that described in Preparation 3, 1-indanone was treated with glyoxylic acid monohydrate and hydrazine hydrate to give [5H]-indeno[1,2-c]pyridazin-3[2H]-one, m.p. 295° (from glacial acetic acid); ν(Nujol mull), 3300-2000, 1660, 1618, 1565 and 738 cm-1 ; δ-(DMSO-d6) 3.95 (2H,s,5-H2), 6.92 (1H,m,4-H), 7.46 (3H,m,6,7,8-H), 7.73 (1H,m,9-H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[N:30]=[N:31][C:32]([CH:34]=O)=[CH:33][C:26]=2[NH:25]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[N:31]=[N:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[CH:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Reactant: O=Cc1cc2c(nn1)SCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CSc2nnc(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)cc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3-carbaldehyde (for a synthesis see WO2004058144, Example 58) (65 mg, 0.33 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (210 mg; 1.0 mmol) was added and the mixture was stirred at room temperature for 4 h. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give 42 mg of the title compound as an oil which solidified to an off-white powder upon standing.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Reactant: OB(O)c1ccccc1
Product: O=C(N1CCC[C@@H]2c3cc(-c4ccccc4)ccc3C[C@@H]21)C(F)(F)F
Yield: 70 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and phenylboronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 70% of theory; LC (method 1): tR=5.02 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([CH:10]([CH2:12][CH3:13])[CH3:11])([C:7](O)=[O:8])[C:4](O)=[O:5])[CH3:2].S(Cl)([Cl:16])=O.[ClH:18]>C(OCC)C>[CH2:1]([C:3]([CH:10]([CH2:12][CH3:13])[CH3:11])([C:7]([Cl:16])=[O:8])[C:4]([Cl:18])=[O:5])[CH3:2]
Reactant: Cl
Reactant: O=S(Cl)Cl
Reactant: CCC(C)C(CC)(C(=O)O)C(=O)O
Solvent: CCOCC
Product: CCC(C)C(CC)(C(=O)Cl)C(=O)Cl

Procedure:
To dry ethyl ether (55.0 ml) under nitrogen was added ethyl 2-(2-butyl)malonic acid (55.0 g, 0.29 mole). Thionyl chloride (32.0 ml, 52.5 g, 0.44 mole) was added dropwise with stirring. The solution was heated to 50° C. for 2 hours under nitrogen, at which time no further HCl was evolved.