Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[CH3:22]I.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[CH2:6][C:5]2([CH3:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(c2ccccc2)CC(=O)Nc2ccc(Cl)cc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC(C)(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-chloro-1,2,3,4-tetrahydro-4-methyl-2-oxo-4-phenylquinolin (6.0 g) in DMF (50 ml) was added sodium hydride (60% in oil) (0.98 g), followed by stirring at room temperature for 30 minutes. After this mixture was cooled to 0° C., methyl iodide (3 ml) was added, followed by stirring at room temperature for further 30 minutes. After dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate. The extract was washed with water and then dried, after which the solvent was distilled off, to yield 6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-2-oxo-4-phenylquinolin as colorless crystals (5.58 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C@@H:13]([CH3:21])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:32][N:33]([CH3:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([N:33]([CH3:32])[CH3:43])=[CH:42][CH:41]=2)[C@@H:13]([CH3:21])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (±)-cis-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (500 mg, 1.68 mmol) in methylene chloride (20 mL) at room temperature was added diisopropylethylamine (542 mg, 749 uL, 4.2 mmol) followed by 4-dimethylaminobenzoyl chloride and stirred at room temperature until no starting material was present. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M (aq) NaOH and brine, dried over sodium sulfate, filtered dried and concentrated. The crude residue was purified by silica gel chromatography (100% hexanes to 70% hexanes/30% ethyl acetate gradient) to afford the amide (665 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12]O)[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)Cl.C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[Na+].[I-]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[N:25]1([CH2:12][CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:8][CH:9]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Nc1ncnn2c(CCO)ccc12
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCN3CCOCC3)ccc12
Temperature: 25 °C
Yield: 24.1 %

Procedure:
To a solution of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (440 mg, 2.5 mmol) in THF (10 ml) and CH2Cl2 anhydrous (10 ml) and was added SOCl2 (0.36 ml, 4.9 mmol) and stirred at rt. After 20 min all starting material was consumed. The crude reaction mixture was concentrated in vacuo to dryness and was suspended in dry CH2Cl2. The solvent was evaporated and the crude was re-suspended in CH2Cl2 and concentrated in vacuo to dryness. The resulting solid was dissolved in DMF (10 ml) and was added triethylamine (0.97 ml, 7.2 mmol), morpholine (1.0 ml, 11.7 mmol) and NaI (280 mg, 1.87 mmol) and heated at 55° C. 24 h. Cooled to rt, the reaction crude was diluted with EtOAc (30 ml) and washed with H2O (2×) and brine (2×), dried over Na2SO4 and concentrated to give yellow solid. The crude was purified by MPLC with 0-10% MeOH/CH2Cl2 to give 149 mg of the titled compound (yield 25%). MS [M+H]+=248; LCMS RT=1.05 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>CO>[CH2:20]([NH:23][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CO
Product: C=CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 54 h
Yield: 30.6 %

Procedure:
To a solution of 1.00 g of 2-chloro-5,6-diphenylpyrazine in 10 ml of methanol, 2.14 g of allylamine was added and the mixture was reacted in a sealed tube at 80° C. for 41 hours, followed by stirring at room temperature for 54 hours. After the solvent was evaporated under reduced pressure, the reaction solution was combined with water, extracted with chloroform, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 330 mg of the desired compound as a pale yellow crystal having a melting point of 97 to 100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]=[N:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH3:23][C:24]([CH3:26])=[CH2:25].B(F)(F)F.CCOCC>C(#N)C>[CH3:23][C:24]1([CH3:26])[C:18]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=2)[NH:7][CH:6]([C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:25]1
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of ethyl 4-(2-nitrobenzylideneamino)benzoate (18.67 g, 62.6 mmol) in acetonitrile was added 2-methylpropene (80 mL, pre-cooled to −78° C.) and boron trifluoride etherate (1 mL) at ice-bath. The reaction mixture was stirred at 90° C. for 18 h in sealed tube. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography to give ethyl 4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as yellow solid (13.4 g, yield 60.4%). %). LC/MS m/e obsd. (ESI+) [(M+H)+] 355.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([I:13])[N:7]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:10][CH:9]=[C:8]([I:13])[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 68.6 %

Procedure:
Under the conditions of example 1 D, 850 mg of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 612 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-5% ethyl acetate. 773 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C([O-])([O-])=O.[K+].[K+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.Cl>[CH2:6]([CH:2]1[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:3]1=[O:5])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(Br)C(=O)O
Reactant: Nc1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCC1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromohexanoic acid (10 mmol, 1951 mg) in DMF (10 ml) was added 2-aminothiophenol (10 mmol, 1252 mg) and K2CO3 (50 mmol, 9.9 g) and the reaction mixture stirred at room temperature for 1 h. EDC (10 mmol, 1917 mg) and HOBt (10 mmol, 1351 mg) were added and the reaction mixture was stirred at room temperature for a further 1.5 h. The reaction mixture was diluted with 1N HCl and extracted with ethyl acetate. The organic phase was washed with sat. NaHCO3, brine, dried over Na2SO4 and then filtered through a short plug of silica gel. Evaporation of the solvent gave product as a yellow solid that was used without further purification. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=222.0; tR=3.07.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:54]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:28][N:27]=[N:26][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[ClH:54]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nnn[nH]2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
In an 4-mL was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (16 mg, 0.043 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) and tetrabutylammonium fluoride trihydrate (20 mg, 0.057 mmol). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml) was added. The precipitate was collected by filtration and washed with water (5 ml) followed dichloromethane (5 ml). After dried, the title compound was obtained as a solid (13 mg, 71% yield, HCl salt, it is regioisomers). MW/HCl=448.41. 1H NMR (DMSO-D6, 360 MHz) δ 8.0 (s, brs, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 4.32 (s, 2H), 2.74 (q, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.11 (t, J=6.8 Hz, 2H). MS: ESI+, m/z 412 [M+H]+. LCMS: 98.6%.
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[C:6](=[CH:8][C:9](Cl)=[CH:10][CH:11]=1)[NH2:7].Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1N)[O:19][CH3:20].[Li]CCCC.Cl>C1COCC1>[NH2:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[C:4]([C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([O:19][CH3:20])[CH:17]=1)=[O:13]
Reactant: COc1ccc(N)c(Br)c1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccccc2N)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
In a flame-dried round bottom flask 4-chloroanthranilic acid N-methoxy-N-methylamide (4.58 g, 21.3 mmol) and m-bromoanisidine (4.02 g, 21.5 g) were dissolved in THF (185 mL) and the resulting solution was cooled to -78° C. With vigorous stirring, 2 equiv of nBuLi in hexanes (26.9 mL, 1.6 M, 43.0 mmol) was added dropwise by a syringe pump at 0.6 mL/min. After 20 min, 40 mL of 1 N hydrochloric acid was carefully added, the mixture was extracted with ethyl acetate (300 mL), and the ethyl acetate was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. Flash chromatography with hexanes/ethyl acetate (95:5, then 75:25) afforded 3.75 g (67% yield) of 2-amino-3'-methoxybenzophenone as a yellow oil. 1H NMR (50 MHz, CDCL3): δ 3.83 (s, 3), 6.17 (b, 2), 6.55 (dd, 1, J=2.0, 8.5), 6.72 (d, 1, J=2.0), 7.06 (dd, 1, J=2.6, 8.5), 7.13 (m, 2), 7.35 (t, 1, J=7.8), 7.39 (d, 1, J=8.5). 2-Amino-4-chloro-3'-methoxybenzophenone was converted to 2-amino-4-chloro-3'-hydroxybenzophenone (below) prior to full characterization.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:4][C:3]1=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:55][C:56]1[CH:60]=[C:59]([C:61]([O:63][CH3:64])=[O:62])[N:58]([CH3:65])[CH:57]=1>CN(C=O)C.CCOCC>[CH3:65][N:58]1[C:59]([C:61]([O:63][CH3:64])=[O:62])=[CH:60][C:56]([NH:55][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3](=[O:20])[CH:4]=2)=[CH:57]1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)CCCCOC2=CC(=O)C(=O)c3ccccc32)cn1C
Reaction time: 0.08 h
Yield: 39.9 %

Procedure:
A solution of an acid 3 (334 mg, 1.22 mmol) in DMF (1.67 mL) was treated with HBTU (462 mg, 1.22 mmol) followed by DIEA (452 mg, 3.5 mmol) and stirred for 5 min. 3-Amino-1-methyl-5-methyloxycarbonylpyrrol hydrochloride (232 mg, 1.22 mmol) and DIEA (378 mg, 3 mmol) were added to the reaction mixture. The latter was stirred for 2 h, diluted with Et2O, the precipitate was removed, dissolved in CHCl3, washed with 3% HCl, H2O, aqueous NaHCO3, H2O again, dried (MgSO4) and purified by chromatography on alumina column (CHCl3/MeOH 80:1, 50:1). The product was triturated with Et2O/CHCl3 to obtain a yellow-red solid (200 mg, 40%); mp 122-123° C. (decomp.): MS (LSIMS, 3-NBA) 410 (M+), 237 (M+−173). 1H NMR (CDCl3) 8.08 (d, J=7.5 Hz, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.34 (s, 1H), 6.65 (d, J=2 Hz, 1H), 5.95 (s, 1H), 4.19 (t, J=5.53 Hz, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 2.46 (t, J=6.6 Hz, 2H), 1.90-2.15 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][N:18]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>[N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[C:2]([C:17]#[N:18])[CH:3]=1
Reactant: CN1CCCC1=O
Reactant: Clc1cnc2c(c1)CCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Product: N#Cc1cnc2c(c1)CCC2
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 3-chloro-6,7-dihydro-5H-[1]pyrindine (7.1 g, 46.2 mmol), sodium carbonate (980 mg, 9.25 mmol), potassium hexacyanoferrate(II)trihydrates (7.81 g, 18.5 mmol), palladium(II) acetate (104 mg, 462 μmol) and butyldi-1-adamantylphosphine (497 mg, 1.39 mmol) was dissolved in N-methyl-2-pyrrolidinone (46.2 ml), the solution flushed with argon and heated to 160° C. for 16 hours. After cooling to 23° C., the mixture was poured into water, extracted with dichloromethane, the combined extracts dried over sodium sulphate and the solvent evaporated leaving a dark blue liquid. The crude material was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the 6,7-dihydro-5H-[1]pyrindine-3-carbonitrile as a white solid (4.82 g, 72% yield). MS (ISP): m/z=145.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCCCCC>O1CCCC1>[OH:22][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(C2(O)CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of 4-bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (54 mL) at −78° C. was added n-butyllithium (19.1 mL of 1.6 M in hexanes, 30.6 mmol) dropwise while maintaining the internal temperature below −65° C. The mixture was stirred at −78° C. for 30 min. Cyclohexanone (1.55 mL, 14.9 mmol) was added dropwise while maintaining the reaction temperature below −65° C. The mixture was stirred at −78° C. for 10 min then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and 1N HCl (25 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred with 1:1 dichloromethane/hexane (20 mL) to provide a white solid, which was filtered and discarded. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-5% methanol/dichloromethane) to provide an off-white solid. The solid was stirred with hexane, filtered, and dried to provide 4-(1-hydroxycyclohexyl)benzoic acid (375 mg, 11%). ESI-MS m/z calc. 220.1. Found 221.3 (M+1)+; Retention time: 1.18 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 1.81-1.46 (m, 9H), 1.35-1.17 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.Cl>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:11]([N:8]1[C:6]2=[N:7][C:2]([C:26]3[CH:27]=[C:22]([OH:21])[CH:23]=[CH:24][CH:25]=3)=[N:3][C:4]([N:13]3[CH2:19][CH:18]4[O:20][CH:15]([CH2:16][CH2:17]4)[CH2:14]3)=[C:5]2[CH:10]=[N:9]1)[CH3:12]
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3cccc(O)c3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (80 mg, 0.27 mmol), 3-hydroxyphenylboronic acid (56 mg, 0.41 mmol), and tetrakis(triphenylphosphine)palladium(0) (35 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (1 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was acidified with concentrated hydrochloric acid and then concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column to provide 3-[1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol MS (ES+): 352.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(OC(C)(C)C)=O.Cl.N1C=CN=C1C=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:36][C:35]4[NH:31][CH:32]=[CH:33][N:34]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Agent: Cl
Agent: O=Cc1ncc[nH]1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(Cc4ncc[nH]4)CC3)cc2n1

Procedure:
ia 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine, prepared from 1-BOC-piperazine followed by treatment with HCl and subsequent reaction with imidazole-2-carboxaldehyde using standard reductive amination conditions. The amine, 2-chloro-6-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was subsequently isolated.
Reaction SMILES: O[Li].O.OO.C([C@H]1COC(=O)N1[C:19](=[O:40])[C@@H:20]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:21]N(C(C)C)C(=O)OC(C)(C)C)C1C=CC=CC=1.[O-:41]S([O-])=O.[Na+].[Na+]>O.C1COCC1>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:20]([CH3:21])[C:19]([OH:40])=[O:41])=[CH:38][CH:37]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
LiOH—H2O (168 mg, 4.00 mmol) was added to a stirring solution of THF (30 mL) and water (15 mL) at room temperature until it was dissolved. The mixture was treated with hydrogen peroxide (658 uL of a 35% wt. solution in water, 8.00 mmol) and allowed to stir at room temperature for 10 minutes. The reaction was cooled to 0° C. in an ice bath, and the tert-butyl (S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (1.00 g, 2.00 mmol) was added dropwise via addition funnel as a solution in THF (15 mL) over a 10 minutes. The mixture was allowed to stir overnight at room temperature to completion by LCMS analysis of the crude. The reaction was cooled to 0° C., and then treated with 1M Na2SO3 (9.00 mL) solution via addition funnel over a ten minute period. After the addition was complete, the mixture was allowed to warm to room temperature for 10 minutes. The mixture was concentrated to remove the THF, and then diluted with water. The aqueous layer was washed twice with ethyl acetate (discarded). The aqueous layer was partitioned with ethyl acetate, then treated dropwise while stirring with 1M HCl until pH 2-3 was attained. The aqueous layer was extracted twice with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The colorless oil product was dried under high vacuum for one hour to afford (S)-3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)propanoic acid as a viscous oil/foam (685 mg, 100%). LC/MS (APCI+) m/z 242.1 [M−Boc]+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH:33]=O)[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:33][C:30]3[CH:29]=[C:28]([CH3:27])[O:32][N:31]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cc(C=O)no1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CC2=C(O)CC(CCc3ccc(OC(C)C)c(F)c3)(C3CCCC3)OC2=O)no1

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 of Example B(14), to 5-Methyl-isoxazole-3-carbaldehyde using the AlCl3/reduction procedure described for Example B(13). 1H NMR (CDCl3): δ 1.32 (d, J=6 Hz, 6H), 1.44-1.92 (brm, 8H), 2.05 (m, 2H), 2.44-2.88 (m, 8H), 2.95 (s, 3H), 4.47 (m, 1H), 6.72-6.92 (m, 2H), 7.66 (m, 2H). ESIMS (MH+): 458.3
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1.Br.[CH2:26]([N:29]=[C:30]=[S:31])[CH2:27][CH3:28].C(OC(C)C)(C)C>COCCO.O>[CH2:26]([NH:29][C:30]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)=[S:31])[CH2:27][CH3:28]
Reactant: CCCN=C=S
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Agent: Br
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CCCNC(=S)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
Triethylamine (2.0 g) was added to 60 ml of a suspension containing 5.04 g of 2-amino-5-[pyridazin-3(2H)-on-6yl]indane·hydrobromide suspended in 2-methoxyethanol, and the mixture was stirred for 10 minutes. Then, 2.33 g of propyl isothiocyanate was added dropwise to the mixture, and the resulting mixture was stirred at 50° C. for 7 hours. After cooling, 100 ml of water and 300 ml of isopropyl ether were added to the reaction mixture, and the resulting mixture was stirred. Crystals precipitated were collected by filtration, washed with water and dried. The crystals obtained were recrystallized from ethanol to obtain 4.53 g of 2-[(propyl)thiocarbamoyl]amino-5-[pyridazin-3(2H)-on-6yl]indane.