Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][Cl:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][Cl:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCCl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC/C=C\CCCl

Procedure:
5.7 of 6-chlorohex-3-yn-1-ol t-butyldimethylsilyl ether in 50 ml of ethanol was hydrogenated under 1 atmosphere of hydrogen in the presence of 0.3 g of Lindlar catalyst until 370 ml of hydrogen had been absorbed. The catalyst was removed by filtration through celite and the ethanol evaporated in vacuo. The crude product was chromatographed on 200 g of silica gel, eluting with 1-4% ether/hexane. Distillation of the appropriate fractions gave 3.7 g of 6-chlorohex-3Z-en-1-ol t-butyldimethylsilyl ether, bp 80° C./0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11](O)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:30][C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[CH:33][N:32]=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([NH:37][C:35]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:30])[CH:36]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Reactant: Cc1cc(N)ccn1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)Nc4ccnc(C)c4)cnc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.2 %

Procedure:
6-Chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (150 mg, 0.37 mmol) in SOCl2 (2 mL) was heated at 60° C. for 1 hour. The reaction mixture was concentrated, dried under reduced pressure and dissolved in DCM (3 mL). 2-Methylpyridin-4-amine (45 mg, 0.41 mmol), and TEA (0.16 mL, 1.11 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours, concentrated and then purified by silica gel chromatography (5% MeOH in DCM) to obtain 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (102 mg, 55% yield) as a yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.263 minutes. [M+H]=499.06.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[OH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OCCCc1cccc(B(O)O)c1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(CCCO)c4)nc23)CCCCC1

Procedure:
{2-[3-(3-Hydroxy-propyl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 3-(3-hydroxypropyl)phenylboronic acid following general procedures as described in these Examples. MP 80-83° C., M+H=378.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:33][C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:35]=2)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]=[C:7]([N:13](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[C:6]=2[N:32]=1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[N:4]([CH2:33][C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[CH:35]=2)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]=[C:7]([NH2:13])[C:6]=2[N:32]=1)[CH3:2]
Reactant: CCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(N)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (2.52 g, 4.16 mmol) in trifluoroacetic acid (25 g) was stirred at room temperature for 20 hours. The trifluoroacetic acid was removed under reduced pressure, and the resulting red oil was stirred with aqueous hydrochloric acid (25 mL of 6 N) and ethanol (10 mL) for 30 minutes. The resulting mixture filtered to remove a solid impurity, cooled to 0° C., adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide, and stirred at for 30 minutes. A solid was present and was isolated by filtration and purified by sequential trituration with toluene, trituration with diethyl ether, and recrystallization from acetonitrile to provide 0.6488 g of 2-ethyl-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a white flocculant solid, mp 255.0-256.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[C:3]=1[C:11]1[C:19]2[NH:18][C:17](=[O:20])[NH:16][C:15]=2[CH:14]=[C:13]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[CH:12]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:8]1([C:4]2[C:3]([C:11]3[C:19]4[NH:18][C:17](=[O:20])[NH:16][C:15]=4[CH:14]=[C:13]([C:21]4[C:22]([CH3:27])=[N:23][O:24][C:25]=4[CH3:26])[CH:12]=3)=[C:2]([CH:28]3[CH2:30][CH2:29]3)[CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:9]1
Reactant: OB(O)C1CC1
Reactant: Cc1noc(C)c1-c1cc(-c2c(Br)ccnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(-c2c(C3CC3)ccnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 100 °C
Yield: 34.9 %

Procedure:
4-(4-bromo-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (17 mg, 0.04 mmol) and cyclopropyl boronic acid (100 mg, 1.2 mmol) were dissolved in dioxane (2 mL). To the reaction mixture were added K3PO4 (50 mg, 0.24 mol) and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane (10 mg, 0.012 mmol). The reaction mixture was heated at 100° C. for 3 h. Solvent was evaporated, the residue was dissolved in EtOAc, washed with brine, evaporated organic solvent and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 5.4 mg of 4-(2,4-dicyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][C:28]1[N:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:40]>CN(C=O)C.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:40].[ClH:40].[ClH:40].[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:27][C:28]2[N:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)cc1
Reactant: BrCc1cccnn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2cccnn2)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-phenol (Example 19) (0.2 mmol, 69 mg) in dry DMF (1 mL) was added 3-bromomethyl-pyridazine (0.4 mmol, 70 mg), and potassium carbonate (0.4 mmol, 56 mg). And the mixture was stirred at 80° C. over night. It was then diluted with water/EtOAc. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 1N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (77 mg). LCMS: m/z 435 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.81 and 7.88 (1 H, s), 7.46-7.51 (2 H, m), 7.30-7.41 (3 H, m), 7.20-7.25 (2 H, m), 5.37-5.53 (1 H, m), 5.20 (2 H, s), 3.30-3.53 (4 H, m), 3.12-3.17 (2 H, m), 2.93 (3 H, s), 2.08-2.58 (4 H, m), 1.44-1.53 (2 H, m), 1.24-1.34 (2 H, m), 0.81 (3 H, t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[Br:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=2[Br:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1cccc(N)c1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5.0 g, 21.80 mmol) was dissolved in dry methylene chloride (32 mL) and dry pyridine (4.50 mL). To the reaction mixture was then added thionyl chloride (3.11 g, 26.17 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-3-methyl-phenylamine (as described in J. Org. Chem. 1998, 53, 1170-1176) (4.46 g, 23.99 mmol), dry triethylamine (7.72 g, 76.33 mmol), dry methylene chloride (40 mL), 4-(dimethylamino)pyridine (0.26 g, 2.18 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17](OCC)=O)[N:11]=1)[CH3:8].C1C[O:25]CC1>>[CH2:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:25])[CH3:17])[N:11]=1)[CH3:8]
Reactant: C1CCOC1
Reactant: CCNc1cccc(CC(=O)OCC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNc1cccc(C(C)O)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mechanically stirred solution of LiAlH4 in THF( 1.0 M, 20 mL, 20.4 mmol) was added dropwise a solution of ethyl 2-(ethylamino)-6-pyridylacetate (1 g, 4.1 mmol) in THF (30 mL). After the addition was completed, the reaction mixture was heated to reflux. After 5 hr, the reaction was cooled to 0° C. and quenched with 10% NaOH solution. The solids were removed by filtration, and the filtrate was concentrated in vacuum. The residue was dissolved in CH2Cl2, and the solution was dried (MgSO4) and concentrated. Reconcentration from toluene (3×) gave the title compound as a colorless oil: MS (ES) 167 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[N-:24]=[N+:25]=[N-:26].[Na+].[NH4+].[Cl-]>CCOCC>[N:24]([C@@H:17]1[CH2:16][O:15][C@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20][C@H:19]1[OH:18])=[N+:25]=[N-:26]
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A solution of (1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.05 g, 0.19 mmol) in a 8:1 MeOH/H2O (2 ml) mixture was treated with NaN3 (0.061 g, 0.94 mmol) and NH4Cl (0.022 g, 0.41 mmol) and the resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ether and the organic layer was separated. Evaporation of the washed (saturated aqueous NaHCO3, water) ether extracts afforded a crude solid product. Purification of the product by flash chromatography (Hexane/Ethyl Acetate=4:1) yielded (2S,4R,5R)-5-Azido-2-benzhydryl-tetrahydropyran-4-ol 30a 0.05 g (95%, [α]D=(−) 109.3, c=1, MeOH).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>[Ru].O1CCCC1>[F:1][C:2]([F:11])([F:12])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Ru]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)C(F)(F)F
Yield: 95 %

Procedure:
There are a number of ways of reducing β-ketoesters which have been disclosed. In addition to hydrogenation, reduction with zinc/acetic acid or with borohydride reagents are known. For the hydrogenation reactions reported in the literature, most use ruthenium, nickel, or baker's yeast as catalyst. All use a solvent. F. G. Kathawala et al. in Helvetica Chimica Acta, 69, 803-805 (1986) disclose an example in which 5% platinum on carbon is used as a catalyst for the reduction of various β-ketoesters using methanol as a solvent. T. Fujima et al. in JP 09268146 A2, Oct. 14, 1997 disclose the hydrogenation of ethyl trifluoroacetoacetate using a nickel catalyst in tetrahydrofuran solvent to provide ethyl 4,4,4-trifluoro-3-hydroxybutyrate in 78% yield. N. Sayo et al. in U.S. 4,933,482, Jun. 12, 1990 disclose the hydrogenation of ethyl trifluoroacetoacetate using a ruthenium catalyst in a polar solvent such as an alcohol or tetrahydrofuran to provide ethyl 4,4,4-trifluoro-3-hydroxybutyrate in 95% yield. None of these references disclose or suggest the process of the present invention in which we have discovered that no solvent is necessary for the catalytic hydrogenation.
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]([F:23])([F:22])[F:21])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8]2[N:12]=[CH:13][C:14](I)=[CH:15][C:7]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[F:1][C:2]1[C:3]([C:20]([F:23])([F:22])[F:21])=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8]2[N:12]=[CH:13][C:14]([C:34]3[CH:33]=[N:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:36][CH:35]=3)=[CH:15][C:7]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1cccc(CN2CCNc3ncc(I)cc32)c1C(F)(F)F
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cccc(F)c3C(F)(F)F)CCN4)cn2)CC1
Yield: 31 %

Procedure:
1-[3-Fluoro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (101 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a yellow solid (31% yield). LCMS: m/z=487.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.51 (4H, t, J=4.9 Hz), 3.49 (2H, m), 3.55 (4H, t, J=4.9 Hz), 3.63 (2H, m), 4.65 (2H, s), 5.08 (1H, bs), 6.48 (1H, d, J=1.8 Hz), 6.64 (1H, d, J=8.8 Hz), 7.09 (1H, m), 7.26 (1H, m), 7.45 (2H, m), 7.62 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=2.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>FC(F)(F)C(O)=O.ClCCl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=2)(=[O:42])=[O:41])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C(F)(F)F)c1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (2.0 g, 4.68 mmol) in 20% trifluoroacetic acid/dichloromethane (50 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo, azeotroping three times with toluene (˜20 mL), to give a dark orange oil. The oil was dissolved in dichloromethane (50 mL) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.900 ml, 5.61 mmol) was added followed by diisopropylethylamine (4.09 ml, 23.39 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then solvent removed in vacuo to give a dark orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-45% ethyl acetate in isohexane) to afford (R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (931 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.62 min, m+H=536.2.
Reaction SMILES: [OH-].[Na+].[Na+].[Cl-].[NH2:5][C:6]1[C:11](Cl)=[C:10]([Cl:13])[N:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]=1[Cl:17]>O>[NH2:5][C:6]1[CH:11]=[C:10]([Cl:13])[N:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]=1[Cl:17]
Reactant: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(C(=O)O)c1Cl
Reaction time: 0.5 h

Procedure:
To a 4-liter (L) flask was added 2370 grams (g) of hot water, 250 g of 50 percent by weight NaOH, 30 g of NaCl, and 350 g of wet 4-amino-3,5,6-trichloropyridine-2-carboxylic acid (80 percent). The solution was stirred for 30 minutes (min), filtered through a 1 micron polypropylene film, and transferred to a 5-L feed circulation tank. This solution weighed 3000 g and contained 9.3 percent 4-amino-3,5,6-trichloropyridine-2-carboxylic acid, 2.0 to 2.5 percent of excess NaOH, and 1.0 percent of NaCl.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][O:9][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[C:17]=1[C:18]#[N:19]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1ccc(CO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(F)c2C#N)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 3,4-dimethoxybenzyl alcohol (1.33 gm; 7.9 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 3 hours. The reaction mixture is poured into ice water with vigorous stirring and refrigerated overnight. The resulting precipitate is removed by filtration and dried under vacuum overnight at 30° C. to give 1.81 grams of 2-(3,4-dimethoxybenzyloxy)-6-fluorobenzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([CH3:26])[N:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.CCO.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:26][C:21]1[N:20]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[C:23]([CH3:25])[N:22]=1
Reactant: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)nc(C)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)nc(C)n1
Temperature: 150 °C
Yield: 16.4 %

Procedure:
1-(3-Bromophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-fluoro-1H-isoindol-3-amine (300 mg, 0.73 mmol), pyrimidin-5-ylboronic acid (108 mg, 0.88 mmol), cesium carbonate (713 mg, 2.19 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (59.6 mg, 0.07 mmol) were dissolved in DME:EtOH:water (6:3:1) (5 mL) and heated in a microwave oven for 20 min at 150° C. EtOAc, water and brine were added and the organic phase was collected, dried and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to afford 49 mg (15%) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][CH2:18][CH2:19]Cl)[CH3:16].O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:17][CH2:18][CH2:19][O:7][C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: Cc1ncccc1O
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOc1cccnc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Potassium carbonate (2.20 g, 15.9 mmol) was added to a stirred solution of 3-hydroxy-2-methylpyridine (1.45 g, 13.3 mmol) and 2-chloroethyl ethyl ether (1.75 mL, 15.9 mmol) in DMF (7 mL) and the mixture was stirred at 70° C. overnight. The reaction was not complete and additional 2-chloroethyl ethyl ether (1 equiv.) and potassium carbonate (1 equiv.) were added and the mixture was stirred at 85° C. for 8 h. Water and ethyl acetate were added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 50% ethyl acetate), obtaining 1.80 g (75%) the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28](C)(C)C(C)(C)[O:26]3)=[C:21](C=O)[CH:20]=2)[N:11]=1)(C)(C)C.C([Si](C)(C)OCCNC1C=CC(C#N)=C(OC2C=CC=C(C=O)C=2)N=1)(C)(C)C.[BH4-].[Na+].Cl>CO>[OH:26][B:25]1[C:22]2[CH:23]=[CH:24][C:19]([O:18][C:12]3[N:11]=[C:10]([NH:9][CH2:8][CH2:7][OH:6])[CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:20][C:21]=2[CH2:28][O:29]1
Reactant: CC1(C)OB(c2ccc(Oc3nc(NCCO[Si](C)(C)C(C)(C)C)ccc3C#N)cc2C=O)OC1(C)C
Agent: CC(C)(C)[Si](C)(C)OCCNc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: N#Cc1ccc(NCCO)nc1Oc1ccc2c(c1)COB2O
Reaction time: 8 h
Yield: 29 %

Procedure:
To a clear solution of mixture of 9 and 10 (6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile and 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-(3-formyl-phenoxy)-nicotinonitrile) in MeOH (anhydrous, 200 mL) was slowly added NaBH4 (0.26 g, 6.9 mmol). The reaction was stirred at room temperature for 4 hours, before the addition of HCl solution (1 M, 30 mL). After overnight at room temperature, the solution was slowly evaporated in vacuo. Purification was accomplished by reverse phase Biotage with 5%-100% MeOH/H2O gradient to afford 120 mg (29% yield) of the title compound as a white solid.