Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[OH-].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc(Cn2ccnc2)cc1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Dimethyl sulphoxide (20 mL, dried over 4 Å molecular sieves) was added to potassium hydroxide (2.24 g, 0.04 mol, crushed pellets) and the mixture was stirred for 5 min. Imidazole (0.5718 g, 0.0084 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (3.25 g, 0.013 mol) was added and the mixture was cooled briefly and stirred for a further hour before adding water (20 mL). The mixture was extracted with ether (3×100 mL) and each extract was washed with water (3×50 mL). The combined ether layers were dried over CaCl2 and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CHCl3/MeOH (30:1) plus 0.05% formic acid as eluent yielding the sub-title compound (1.275 g, yield: 53%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=O)(C)(C)C.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>C(#N)C>[NH2:8][C@@H:9]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:10]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: Nc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)[C@H](N)C(=O)Nc1ccccn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.00 g, 4.32 mmol), pyridine-2-amine (1.506 g, 16.00 mmol), DIEA (8.36 mL, 48 mmol), and HATU (7.87 g, 20.80 mmol) were taken up in ACN (5 mL) and heated at 120° C. for 30 minutes under microwave irradiation. ACN was removed under reduced pressure and the residue was dissolved in water and extracted with EtOAc (2×50 mL). The organic extracts were concentrated under reduced pressure and purified by preparative HPLC. Hydrogen chloride (4 M in THF, 4 mL, 16 mmol) was added to the resulting solid and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with EtOAc (2×50 mL). The aqueous layer was basified with 30% NaOH solution. The resulting solid precipitate was removed by filtration. The filtrate was extracted with DCM (2×50 mL). The DCM layer was dried and concentrated to give the title compound (83 mg) as a brown liquid. LCMS m/z=208.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[N:10]=[C:9]([CH3:14])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:11]1[C:3]2[C:2]([NH:15][CH2:16][CH2:17][OH:18])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:14])=[N:10]1)[CH3:13]
Reactant: NCCO
Reactant: CCn1nc(C)c2nc(C)nc(Cl)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(C)c2nc(C)nc(NCCO)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
A solution of 12 g (0.057 mol) of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine in 150 ml of methylene dichloride is treated with 12 g (0.2 mol) of 2-aminoethanol and 8 ml of triethyamine and stirred at room temperature 48 hours. The mixture is filtered to give 7.6 g (56%) of 2-[1-ethyl-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]aminoethanol, mp 181°-183° C. from ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][C:6]2=[O:13])[CH3:2].C(=O)(O)[O-].[Na+].O.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:8][CH2:7][C:6]2=[O:13])[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)CCN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc2c(c1)C(=O)CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one (1.25 g) in THF (15 mL) was added sodium bicarbonate (0.84 g). Water (5 mL) followed by benzyl chloroformate (1.58 g) were added to the mixture,and it was stirred at room temperature overnight. The reaction was not complete as determined by TLC, so an additional 0.60 g of NaHCO3 were added to the mixture and it was stirred at room temperature for two additional hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated. Chromotography on silicia gel using 25% ethyl acetate in heptane solvent solution gave 1.84 g of the title compound. MS (ESI+) for C19H19NO3 m/z 310.03 (M+H)+.
Reaction SMILES: CC1(C)C(C)=CC(C)(C)C2C(=O)CCCC1=2.[CH3:17][C:18]1([CH3:37])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]([CH3:27])([CH3:26])[C:20](=[CH2:28])/[C:19]/1=[C:29](/[O:32][Si](C)(C)C)\[CH:30]=[CH2:31]>>[CH3:26][C:21]1([CH3:27])[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]([CH3:37])([CH3:17])[C:19]2[C:29](=[O:32])[CH2:30][CH2:31][CH2:28][C:20]1=2
Reactant: C=C/C(O[Si](C)(C)C)=C1\C(=C)C(C)(C)C(C)=C(C)C1(C)C
Agent: CC1=CC(C)(C)C2=C(CCCC2=O)C1(C)C
Product: CC1=C(C)C(C)(C)C2=C(CCCC2=O)C1(C)C
Yield: 47 %

Procedure:
As described above for (6a) provided it used (5b) as starting material. Yield: 47%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)[CH:25]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:28]1[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]3[O:31][C:32]([CH3:38])([CH3:37])[C:33]([CH3:36])([CH3:35])[O:34]3)[CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 4.05 g, 15.05 mmol), 4,4,5,5-tetramethyl-2-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane (Intermediate G2, 5 g, 15.05 mmol), X-Phos-Pd-G2 (1.184 g, 1.505 mmol) and K3PO4.H2O (9.81 g, 30.1 mmol) were dispersed in THF (42 ml) and deoxygenated under argon, then water (42 mL) was added and the mixture stirred at rt overnight. The reaction was diluted with AcOEt (250 ml) and washed with 0.2 M of HClaqueous (250 ml), once with saturated NaClaqueous, anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50 G SNAP with a gradient of hexane and AcOEt to give the title compound (5.4 g, 91%) as dark oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[C:18]([C:24](O)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[C:18]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=3[CH:15]=2)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: CC1=C(CO)CCCc2ccc(N)cc21
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ncc(Cl)cc3Cl)cc21

Procedure:
In a manner similar to the procedure of step 3A, (E)-(2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from preparation J was coupled with 3,5-dichloropicolinic acid to afford the titled compound of Step 45A. LCMS (M+H)+=375.2. 1H NMR (500 HMz, methanol-d4) δ 8.62 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.50 (dd, J=8.1, 2.3 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 4.33 (s, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.13-2.08 (m, 2H), 2.00-1.95 (m, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[CH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.I[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[C:29]2=[O:36]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30](=[O:35])[C:29]3=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#CCCN3CCC(Cc4ccccc4)CC3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of 4-benzyl-1-(3-butynyl)piperidine (904 mg, 4 mmol), Et3N (4 mL), CuI (76 mg, 0.4 mmol) and Pd(PPh3)2Cl2 (41 mg, 0.1 mmol) in DMF (10 mL) is stirred at room temperature under N2 for 30 min. 5-Iodoisatin (546 mg, 2 mmol) is added and stirring continued overnight. The mixture is evaporated and the residue purified by medium-pressure column chromatography on silica gel eluting with 50% EtOAc/hexanes (+1% Et3N) to give an orange solid (238 mg). The solid is recrystallized from hot 90:10 isopropanol:water to give the title compound as orange crystals (152 mg): mp 140-141° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.[C:30]([O:34][C:35]([NH:37][C:38]([CH3:43])([C:40]([OH:42])=O)C)=[O:36])([CH3:33])([CH3:32])[CH3:31].[Cl:44][C:45]1[CH:51]=[C:50]([S:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:49]=[CH:48][C:46]=1[NH2:47].[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:44][C:45]1[CH:51]=[C:50]([S:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:49]=[CH:48][C:46]=1[NH:47][C:40](=[O:42])[C@H:38]([NH:37][C:35]([O:34][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:36])[CH3:43]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Nc1ccc(Sc2ccccc2)cc1Cl
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Sc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triphenylphosphine (0.0.612 g) was added to a cooled (−78° C.) solution of hexachloroacetone (0.18 ml) and N-t-butyloxycarbonyl-2-methylalanine (0.441 g) in dry DCM (15 ml) under argon. The resulting mixture was stirred at low temperature for 20 minutes. Then 2-chloro-4-(phenylsulphanyl)aniline (0.5 g) (Method 5) and dry triethylamine (0.33 ml) were added. The resulting mixture was slowly warmed to room temperature, under argon, before being stirred for 1 hour at room temperature. Saturated aqueous ammonium chloride solution (15 ml) was added and the mixture was extracted with DCM (2×50 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel column eluting with 2% ethyl acetate/DCM to give the title compound. NMR (CDCl3): 1.40-1.45 (m, 12H), 4.294.40 (m, 1H), 4.864.95 (m, 1H), 7.20-7.40 (m, 7H), 8.30-8.38 (m, 1H), 8.64 (brs, 1H); MS (ESP−): 405.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].CO.C(OCC)(=O)C>C(O)C>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of 3-[2-(4-ethoxycarbonylphenyl)ethynyl]-3-hydroxyquinuclidine (250 mg) in ethanol (20 ml) was added 4N aqueous sodium hydroxide solution (0.7 ml). The reaction mixture was stirred for 18 hours. The reaction mixture was evaporated and the residue was acidified with 5N hydrochloric acid. The mixture was evaporated to give a solid which was treated with methanol/ethyl acetate to give 3-[2-(4-carboxyphenyl)ethynyl]-3-hydroxyquinuclidine (120 mg), m.p. 288°-290° C.; microanalysis, found: C, 59.4; H, 5.8; N, 4.1; Cl, 13.1%; C16H17NO3.0.5NaCl. 0.5HCl requires: C, 60.3; H, 5.53; N, 4.39; Cl, 11.1%; NMR: 1.66-1.82(1H,m), 1.86-2.31(4H,m), 3.03-3.45(5H,m), 3.51-3.63(1H,d), 6.55(1H,s), 7.54-7.62(2H,d), 7.89-7.98(2H,d), 12.1(1H,br); m/z 272(M+H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:25])[C:20]2([CH3:22])[O:21][CH:19]2[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:23]#[N:24])[CH:17]=2)[O:12]1.B(F)(F)F>C1COCC1>[CH3:10][C:11]1([CH3:25])[C:20]([CH3:22])([OH:21])[CH:19]([O:6][C:3]2[CH2:4][CH2:5][C:1](=[O:7])[CH:2]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:23]#[N:24])[CH:17]=2)[O:12]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21C
Reactant: O=C1CCC(=O)C1
Agent: FB(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2C(OC2=CC(=O)CC2)C1(C)O
Reaction time: 1 h

Procedure:
2.1 g of 1,3-cyclopentanedione are dissolved in 200 ml of THF under N2, 650 mg of NaH (80% in mineral oil) are added, the mixture is stirred for 1 hour, a solution of 4.6 g of 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman ("IIa") in 20 ml of THF, then 2.4 ml of BF3 etherate are added successively and the mixture is stirred overnight at 20°. The mixture is evaporated and the 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-cyano-3-chromanol ("A") obtained is purified by chromatography on silica gel (ethyl acetate/methanol 100:1); m.p. 204°-206° (from isopropanol).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
To a stirred solution of 1.8 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of triethylamine in 100 ml of methylene chloride at 0° C. is added a solution of 2.8 g of 4-iodobenzoyl chloride in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 4 hours and evaporated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na2SO4, filtered and evaporated in vacuo to a brown residue which is crystallized from ether-hexane to give 3.0 g of the desired product. Mass spectrum: M+H:323.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[CH:3][C:2]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Nc1ccccc1
Reactant: COc1ccc(-c2ncc(Br)cn2)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncc(Nc3ccccc3)cn2)cc1F
Temperature: 100 °C

Procedure:
In a 50 mL round bottom flask under nitrogen was charged 5-bromo-2-(3-fluoro-4-methoxyphenyl)pyrimidine (Step 1, 0.40 g, 1.41 mmol), aniline (0.28 g, 3.0 mmol), Pd(OAc)2, (0.015 g, 0.067 mmol), BINAP (0.090 g, 0.064 mmol), and NaOtBu (0.27 g, 2.8 mmol). Toluene (5.0 mL) was added and the mixture was heated at 100° C. for 24 h. The mixture was cooled to RT and was partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4 and concentrated. Purification on silica with 1% MeOH in CH2Cl2 afforded the title compound as a purple solid. MS (ESI pos. ion) m/z: 296. Calc'd for C17H14FN3O: 295.11.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:54][C:55]4[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=4)=[O:18])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Reactant: Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[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: Cc1cccc(NC(=O)c2ccc(N3CCc4nc(N)ncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.1 %

Procedure:
A mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 1.0 mL DMF was stirred at room temperature for 10 minutes. Then meta-toluidine (0.022 mL, 0.20 mmol) was added and the reaction heated at 55° C. for 18 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (18 mg, 51%). 1H NMR (DMSO-d6) δ: 9.84 (s, 1H), 8.12 (s, 1H), 7.85-7.92 (m, 2H), 7.60 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.03-7.09 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 6.42 (s, 2H), 4.36 (s, 2H), 3.71 (t, J=6.0 Hz, 2H), 2.75 (t, J=5.9 Hz, 2H), 2.30 (s, 3H)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH:33]=[CH2:34])=[C:22]([C:24]2[N:28]3[N:29]=[CH:30][CH:31]=[CH:32][C:27]3=[N:26][CH:25]=2)[CH:23]=1)=[O:18])(C)(C)C.C([O-])=O.[NH4+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(O)CC.[Pd]>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH2:33][CH3:34])=[C:22]([C:24]3[N:28]4[N:29]=[CH:30][CH:31]=[CH:32][C:27]4=[N:26][CH:25]=3)[CH:23]=2)=[O:18])[C:10]([F:15])([F:14])[CH2:11][CH2:12][CH2:13]1
Reactant: C=Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnc2cccnn12
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: CCc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
tert-Butyl[(1R,2R)-2-({[5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (103 mg, 0.205 mmol), ammonium formate (128 mg, 2.04 mmol), and 10% Pd/C (109 mg, 0.102 mmol) were dissolved in n-propanol (4.1 mL) and left to stir at 100° C. for 18 h. The solution was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and taken up in dichloromethane (2 mL). Trifluoroacetic acid (1 mL, 13.0 mmol) was added to the mixture and stirred for 4 h at room temperature. The solution was then neutralized with aqueous saturated sodium bicarbonate and extracted with dichloromethane (×3). The organic layers were collected and dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by prep HPLC. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with dichloromethane. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.60 (d, 1H); 8.22 (s, 1H); 8.21 (d, 1H); 7.95 (s, 1H); 7.90 (d, 114, br); 7.29 (dd, 1H); 4.56 (m, 1H); 3.08 (m, 1H); 2.83 (q, 2H); 2.10 (m, 1H); 1.86 (m, 1H); 1.71 (m, 1H); 1.59 (m, 2H); 1.44 (m, 1H); 1.20 (t, 3H). LRMS (APCI) calc'd for (C19H21F2N5OS) [M+H]+, 406.1. found 406.1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[S:10](Cl)([CH3:13])(=[O:12])=[O:11].Cl>C1COCC1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(S(C)(=O)=O)CCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of (2R)-2-methylpiperazine (1.00 g, 9.98 mmol) in NaOH (2 M aqueous, 10.5 ml, 21.0 mmol) and THF (15 ml) at 0° C. was added a solution of mesyl chloride (0.817 ml, 10.5 mmol) in THF (5 ml) over 30 seconds. The clear solution was stirred at 0° C. for 2 h. The reaction was poured into 2M aqueous HCl (20 ml), then the mixture washed with EtOAc (2×25 ml). The aqueous was adjusted to pH 12 with solid NaOH (˜1.5 g), then extracted with DCM (2×25 ml). The combined organics were passed through a phase separator and concentrated under vacuum to leave a white solid, (3R)-3-methyl-1-(methylsulfonyl)piperazine (352 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)C.C([BH3-])#N.[Na+]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:21]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc(N2CCNCC2)ccc1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(c3ccc(C4CCCCC4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a solution of N-tert-butoxycarbonyl-4-piperidinone (3.3 g) and 1-(4-cyclohexylphenyl)piperazine (4.0 g) in dichloromethane (20 ml) was added titanium(IV)isopropoxide (8 ml) and the mixture was stirred at ambient temperature for 2 hours. Then, to the reaction mixture was added ethanol (20 ml) and sodium cyanoborohydride (1 g) in several portions, the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was pulverized with water. The precipitate was filtered off and the filtrate was extracted with dichloromethane. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure and chromatographed (Silica gel 60 (Trademark: prepared by Merck)) eluting with hexane/ethyl acetate to afford 1-tert-butoxycarbonyl-4-[4-(4-cyclohexylphenyl)piperazin-1-yl]piperidine (1.35 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[CH2:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[F-].[K+]>CS(C)=O>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])=[N:7][C:2]=1[NH:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])#[N:23]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(C#N)cc2F)c1
Reactant: CC(C)(C)CN
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(NCC(C)(C)C)c(C#N)cc2F)c1
Temperature: 150 °C
Yield: 1.8 %

Procedure:
A mixture of 3-(6-chloro-5-cyano-3-fluoro-pyridin-2-ylamino)-N-methoxy-4-methyl-benzamide (52 mg, 0.15 mmol), neopentylamine (0.12 mL) and potassium fluoride (12 mg) in DMSO (1 mL) was heated to 150° C. overnight. The product (1.1 mg, 1.8%) was isolated after purification by HPLC. C20H24FN5O2 MS m/e=386 (M+H).