Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([O:30][CH3:31])=[C:6]([CH:29]=1)[CH2:7][O:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:31][O:30][C:5]1[C:6]([CH2:7][O:8][CH2:9][C:10]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:29][C:2]([C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)=[CH:3][C:4]=1[CH3:32]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1c(C)cc(Br)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2ccc(C#N)cc2)cc1COCC1(c2ccccc2)CCNCC1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (65 mg, 0.13 mmol), 4-cyanophenylboronic acid (76.4 mg, 0.52 mmol), and tetrakis(triphenylphosphine) palladium(0) (20 mg, 0.01 mmol) were combined in dry tetrahydrofuran (2 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.46 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 28 mg (51%). 1H-NMR (CDCl3, 500 MHz) δ 7.69 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.36 (s, 1H), 7.27-7.30 (m, 3H), 7.17-7.20 (m, 2H), 4.46 (s, 2H), 3.61 (s, 3H), 3.50 (s, 2H), 2.89-2.92 (m, 2H), 2.72-2.76 (m, 2H), 2.31 (s, 3H), 2.16-2.19 (m, 2H), 1.88-1.93 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 157.1, 145.4, 144.4, 134.7, 132.5, 132.4, 131.7, 129.2, 128.3, 127.6, 127.4, 126.1, 125.8, 119.1, 110.6, 80.2, 68.2, 60.9, 42.7, 41.9, 33.6, 16.2. Mass spec.: 427.42 (MH)+. Accurate mass spec.: m/z 427.2378 [MH]+, Δ=1.8 ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[Na+].O>CO>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: CC(C)c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNc1ccc(C(C)C)cc1

Procedure:
A solution of 4-isopropylaniline (5.05 g, 37.3 mmol), methyl bromoacetate (5.99 g, 39.2 mmol) and anhydrous sodium acetate (3.21 g) in absolute methanol (30 mL) was heated to reflux for 2 h. The solution was cooled and poured into 300 mL water. The resulting solid was collected by filtration and recrystallized from ethanol/water to afford pure product, methyl-2-(4-isopropylanilino)acetate, m.p. 35-36° C. (4.53 g, 55%). 1H NMR (CDCl3, 300 MHz): δ 7.06 (2H, d, J=8.2 Hz), 6.57 (2H, d, J=8.2 Hz), 4.18 (1H, v br), 3.90 (2H, s), 3.78 (3H, s), 2.81 (1H, m, J=7.0 Hz), 1.20 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 209 (3), 208 (31), 148 (100).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:23][C:18]1[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]2[O:14][C:13]([CH3:26])([CH3:25])[CH:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=3)[C:16]=2[C:17]=1[CH3:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 68 mg, 1.70 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (0.5 g, 1.54 mmol) in N,N-dimethylformamide (20 mL) at 0° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction mixture was added benzyl bromide (290 mg, 1.70 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured Into water (30 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (380 mg, yield 60%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.Cl.[NH:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH3:34].C(N(CC)CC)C.O>C1COCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([N:33]([CH3:34])[CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:7]([C:8]#[N:9])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:30][CH:29]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
100 mg (0.21 mmol) of the compound from Example 46A were dissolved in 2 ml of dry THF. 57 mg (0.41 mmol) of methyl sarcosinate hydrochloride and 86 μl (0.62 mmol) of triethylamine were then added in succession. The reaction mixture was stirred at RT for 10 h. 1 ml of water was added, and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were washed once with 3 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]1([C@H:7]([NH:19][C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])[C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][C:13](O)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=1>>[OH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([NH:31][C:13](=[O:14])[CH2:12][O:11][C:10]2[CH:9]=[C:8]([C@@H:7]([NH:19][C:20](=[O:21])[O:22][C@@H:23]3[CH:28]4[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]4)[CH2:24]3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:33][CH:34]=1
Reactant: Nc1ccc(CO)cc1
Reactant: O=C(O)COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Product: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1ccc(CO)cc1

Procedure:
The title compound was prepared as described in Example 1 Step 10 with 2-(3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)acetic acid replacing 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl) phenoxy)methyl)benzoic acid and 4-aminobenzyl alcohol replacing 4-(2-hydroxyethoxy)-3-methylbenzaldehyde.
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[N+:20]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)(=[O:30])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NOC2CCCC2)c1
Reaction time: 2.5 h
Yield: 78.8 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 112.99 mmol) in anhydrous tetrahydrofuran (25 mL) under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 2.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 3-nitro-1-benzenesulphonyl chloride (3.17 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (3.224 g, 87%) as a solid. H1-NMR (chloroform-D3): 1.71 (m, 8H), 4.71 (m, 1H), 6.93 (bs, 1H), 7.83 (m, 1H), 8.28 (m, 1H), 8.55 (m, 1H), 8.81 (m, 1H)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CC(O)=O>[CH2:2]([O:3][C:4]([C@H:6]1[CH2:12][CH2:11][C@H:9]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-cyclohexanonecarboxylic acid ethyl ester (5.0 g, 29.0 mmol) and tert-butyl carbazate (3.9 g, 29.4 mmol) in dichlorometane (250 mL) and AcOH (4 mL) was added NaBH(OAc)3 (18.7 g, 88.0 mmol) gradually at 0° C. After addition, the mixture was stirred at the same temperature for 3 h, then allowed to warm to room temperature and stirred for 20 h. The reaction mixture was poured into saturated aqueous Na2CO3 solution and extracted with DCM. The DCM extracts were washed with brine×2 and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound D1-1 (3.0 g, 36%) as a white solid.
Reaction SMILES: C#CCC.[CH2:5]([C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22]2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][CH2:8]CCCCCC.C1(C)C=CC=CC=1>CCCCCC>[C:5]([C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22]2)=[CH:17][CH:16]=1)#[C:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCc1ccc2ccc(OC)cc2c1
Agent: C#CCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC#Cc1ccc2ccc(OC)cc2c1
Yield: 56 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and butyne gas (a product manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD., 100 g, large excess), 7-butyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-butyn-1-yl-2-methoxynaphthalene (18.1 g, yield of 56%). The obtained 7-butyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (275 ml) under a hydrogen atmosphere by adding 10% Pd/C (1.83 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-butyl-2-methoxynaphthalene (compound (3)-04, 17.80 g, yield of 97%).
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][CH2:13][CH2:14]O)[C:9](=[C:16]=[CH2:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:18].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>CO.Cl[Pd]Cl>[C:1]1([CH:7]2[O:11][CH:10]3[C:9]([C:16](=[CH2:17])[C:19]([O:22][CH2:23][CH3:24])=[O:21])([O:18][CH2:14][CH2:13][CH2:12]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: O
Reactant: C=C=C1CC(c2ccccc2)OC1CCCO
Agent: Cl[Pd]Cl
Solvent: CO
Product: C=C(C(=O)OCC)C12CC(c3ccccc3)OC1CCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(5-phenyl-3-vinylidene-tetrahydrofuran-2-yl)propan-1-ol (66 mg, 0.29 mmol) was dissolved in 2 mL of methanol, and then was filled with CO gas (1 atm), followed by addition of PdCl2 (5.2 mg, 0.029 mmol) and CuCl2 (117 mg, 0.87 mmol). The solution was stirred for 4 hours at room temperature. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:25, v/v), thus providing products (56 mg, 65%).
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[F:15][C:16]([F:57])([F:56])[C:17]1[CH:18]=[C:19]([NH:27][C:28](=[O:55])[NH:29][C:30]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][C:31]=2[O:32][C:33]2[CH:41]=[CH:40][C:39]([C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[CH:38][C:34]=2[C:35]([O-:37])=[O:36])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>C(OCC)(=O)C.[Pd]>[F:15][C:16]([F:56])([F:57])[C:17]1[CH:18]=[C:19]([NH:27][C:28](=[O:55])[NH:29][C:30]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][C:31]=2[O:32][C:33]2[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:46])[CH2:43][CH3:44])=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)[O-])c1
Agent: [Pd]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)O)c1
Reaction time: 16 h

Procedure:
Benzhydrol-2-[2-[3-[3,5-bis(trifluoromethyl)phenyl]ureido]-4trifluoromethylphenoxy]-5-(1,1-dimethylpropyl)benzoate (110 mg, 0.0002 mol) was dissolved in ethyl acetate and a palladium on carbon catalyst (50 mg) was added, under argon. The mixture was hydrogenated in a parr bottle at 54 psi, for 16 h. The mixture was filtered through Celite® and washed with ethyl acetate and methanol. The solvents were evaporated and the residue was flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the title compound; mp 238°-240° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[N:3]=1.[NH2:33][C:34]1[C:39]([NH:40][C:41]([C:43]2([N:46]3[C:50]([CH3:51])=[CH:49][CH:48]=[N:47]3)[CH2:45][CH2:44]2)=O)=[CH:38][CH:37]=[C:36]([N:52]2[CH2:57][CH2:56][CH2:55][C@@H:54]([C:58]([N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:59])[CH2:53]2)[N:35]=1.C[O-].[Na+].C(O)C(C)C>CO>[CH3:19][C:16]1[CH:17]=[CH:18][N:14]([C:11]2([C:9]3[NH:1][C:2]4=[N:3][C:4]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[O:27])[CH2:21]5)=[CH:5][CH:6]=[C:7]4[N:8]=3)[CH2:13][CH2:12]2)[N:15]=1.[CH3:51][C:50]1[N:46]([C:43]2([C:41]3[NH:33][C:34]4=[N:35][C:36]([N:52]5[CH2:57][CH2:56][CH2:55][C@@H:54]([C:58]([N:60]6[CH2:64][CH2:63][CH2:62][CH2:61]6)=[O:59])[CH2:53]5)=[CH:37][CH:38]=[C:39]4[N:40]=3)[CH2:45][CH2:44]2)[N:47]=[CH:48][CH:49]=1
Reactant: Cc1ccn(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)n1
Reactant: Cc1ccnn1C1(C(=O)Nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2N)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CO
Product: Cc1ccn(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)n1
Product: Cc1ccnn1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 110 °C

Procedure:
Into a vial containing (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(3-methyl-1H-pyrazol-1-yl)cyclopropanecarboxamide or (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(5-methyl-1H-pyrazol-1-yl)cyclopropanecarboxamide (60 mg, 0.14 mmol) and sodium methoxide (25% wt in methanol, 118 μL) was added isobutanol (0.4 mL) and methanol (0.2 mL). The reaction mixture was heated to 110° C. for 5 h. The solvent was removed under reduced pressure and the residue was purified via HPLC to afford (R)-(1-(2-(1-(3-methyl-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone or (R)-(1-(2-(1-(5-methyl-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Example 89, starting from Intermediate 10): MS (ESI+) (M+H) 420.3; HPLC retention time 1.85 min (Method A).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Fc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.50 g, 9.09 mmol), thionyl chloride (20 ml) and a catalytic amount of DMF (2 drops) was stirred under reflux for 1.5 h to give a homogeneous mixture. It was evaporated under reduced pressure at 50° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3,4-dichloroaniline (1.62 g, 10.0 mmol) in dry DMA (15 mL). The residue of 3,4-dichloroaniline was washed down with more DMA (2×2 ml). The reaction mixture was stirred at room temperature for 20 h. It was poured into water (200 mL). The pH was adjusted to ca. 8 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether. The solid was collected by filtration and washed with water (5×25 mL). It was dried in vacuum over silica gel/KOH overnight to give N-(3,4-dichlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (204) (2.81 g, 100%) as a yellow/orange solid, mp 262-264° C.; 1H NMR δ [(CD3)2SO] 10.17 (s, 1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.26 (poorly resolved d, J=0.7 Hz, 1H), 7.92 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H). Anal. Calcd for C13H7Cl2FN4: C, 50.51; H, 2.28; N, 18.12. Found C, 50.50; H, 2.27; N, 18.42.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:6]2[C:7](=[O:20])[C:8]([N:11]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:14]=4[CH:13]=[CH:12]3)=[CH:9][CH:10]=[C:5]2[C:4](=[O:21])[NH:3]1.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:22])[N:6]2[C:7](=[O:20])[C:8]([N:11]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:14]=4[CH2:13][CH2:12]3)=[CH:9][CH:10]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: [H][H]
Reactant: CC1(C)NC(=O)c2ccc(-n3ccc4cncnc43)c(=O)n21
Agent: [Pd]
Solvent: CO
Product: CC1(C)NC(=O)c2ccc(N3CCc4cncnc43)c(=O)n21

Procedure:
To a stirred solution of 3,3-dimethyl-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (1, 0.095 g, 0.32 mmol) in methanol (25 ml), 10% palladium on carbon (25 mg) was added. The reaction mixture was hydrogenated under balloon pressure hydrogen gas for 24 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain a crude residue. The residue was purified by prep HPLC to afford the product as a light yellow solid. Yield: 8.0 mg, 8%; MS (ESI) m/z 298.20 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.17 (t, J=8.6 Hz, 2H), 3.13 (t, J=8.6 Hz, 2H), 2.59 (s, 2H), 1.79 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:30][CH2:31][CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=2)(=[O:37])=[O:36])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)=[CH:12][C:11]=1F)#[N:9].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([C:10]1[C:15]2=[CH:14][C:13]([C:16]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)([C:17]3[NH+:18]([CH3:22])[CH:19]=[N:20][CH:21]=3)[NH2+:30][CH2:31][CH2:32][CH2:33][NH:34][S:35](=[O:37])(=[O:36])[C:38]3[CH:39]=[C:40]([O:44]2)[CH:41]=[CH:42][CH:43]=3)=[CH:12][CH:11]=1)#[N:9]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1cncc1C(NCCCNS(=O)(=O)c1cccc(O)c1)(c1ccc(F)cc1)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[NH+]1C=NC=C1C1(c2ccc(F)cc2)[NH2+]CCCNS(=O)(=O)c2cccc(c2)Oc2cc1ccc2C#N
Product: O=C([O-])C(F)(F)F
Reaction time: 3 h

Procedure:
N-(3-{[1-(4-Cyano-3-fluoro-phenyl)-1-(4-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-methyl]-amino}-propyl)-3-hydroxy-benzenesulfonamide trifluoroacetate salt (0.105 g, 0.137 mmol) was dissolved in DMF (20 mL) and treated with Cs2CO3 (0.223 g, 0.69 mmol). After 3 h at 80° C., the reaction mixture was concentrated in vacuo, dissolved in H2O: 0.1% TFA (3 mL), purified by RP LC on a Delta PrepPak eluting with 95:5 to 5:95 H2O(0.1%TFA): CH3CN(0.1%TFA) and lyophilized to give the title compound. MS (M+1) 518.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=[CH:9][C:10]=1[F:11])(=[O:3])[CH3:2].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH2:33])[CH:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH:33][C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]2[CH:8]=[CH:9][C:10]([F:11])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH:26]=[N:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc2cnn(Cc3ccccc3)c12
Reactant: CC(=O)Oc1cc(/C=C/C(=O)O)ccc1F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(/C=C/C(=O)Nc2cccc3cnn(Cc4ccccc4)c23)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 8.3 %

Procedure:
A mixture of (E)-3-(3-acetoxy-4-fluoro-phenyl)-acrylic acid (119 mg, 0.53 mmol), 1-benzyl-1H-indazol-7-ylamine (118 mg, 0.53 mmol), EDC (123 mg, 0.64 mmol) and HOBT (36 mg, 0.27 mmol) in DMF (3 ml) was stirred at RT for 48 hrs. The mixture was then diluted with water and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to dryness. The crude was purified by column chromatography (petroleum ether: AcOEt from 9:1 to 1:1) to give the title (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(4-fluoro-3-acetoxy-phenyl)-acrylamide (19 mg).