Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[C:9]([N:13]1[C:18](=[O:19])[C:17]([CH:20]2[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]2)=[C:16](Cl)[CH:15]=[N:14]1)([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([N:13]1[C:18](=[O:19])[C:17]([CH:20]2[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]2)=[C:16]([NH:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[N:14]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC1CCOC(c2c(Cl)cnn(C(C)(C)C)c2=O)O1
Reactant: NCc1ccncc1
Solvent: CCO
Product: CC1CCOC(c2c(NCc3ccncc3)cnn(C(C)(C)C)c2=O)O1

Procedure:
Into 20 ml of an absolute ethanol solution of 2.7 g of 4-picolylamine, 20 ml of an absolute ethanol solution of 3.4 g of 2-tert-butyl-5-chloro-4-(4-methyl-1,3-dioxan-2-yl)pyridazin-3-(2H)-one was dropwise added at room temperature. The mixture was reacted overnight under heating and refluxing and then left to cool. Ethanol was distilled off under reduced pressure, and then 150 ml of ethyl acetate was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was subjected to column chromatography. Using an eluent (ethyl acetate:methanol=30:1 to 12:1), 1.2 g of the desired product (Compound No. 44) having a melting point of from 150° to 153° C. and 0.18 g of amorphous 4-tert-butyl-5-(4-pyridylmethylamino)-4-(4-pyridylmethyliminomethylidenyl)pyridazin-3-(2H) -one (Compound No. 2) as a by-product, were obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[S:22]1C2C(=CC=CC=2)C(N)CC1>>[S:22]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]([NH:11][C:4]2[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=2)[CH2:13][CH2:14]1
Reactant: NC1CCSc2ccccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCSc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,4-dihydro-2H-thiochromen-4-ylamine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.71, 7.30, 7.15, 7.05, 5.44, 4.51, 3.17, 2.98, 2.68, 2.64, 2.56, 2.14, 1.31; HRMS (FAB) calcd for C17H21N3S+H 300.1534, found 300.1532.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][OH:22].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][NH:19][CH2:20][CH2:21][O:22][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CNCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CNCCOc1ncccc1OCCO
Reaction time: 48 h
Yield: 14.4 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(methylamino)ethanol (47 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of 1.0 M NaOH and 1 mL of brine. The organic phase was shaken with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of chloroform. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 12 mg (0.056 mmol, 14%) of the title compound as a colorless oil. LC-UV purity 90%. MS m/z 213 (M+1)+, calc. 213 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[Cl:22][CH2:23][C:24]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([O:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[N:1]=1
Reactant: COc1cc(N)c(C(=O)Nc2ccccc2Cl)cc1OC
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 45.8 %

Procedure:
Prepared according to Procedure B with 1a (2.95 g, 9.63 mmol) and chloroacetyl chloride (2.3 mL, 28.9 mmol) in acetic acid (30 mL). Purified by extraction from aq. K2CO3 and recrystallization from isopropanol to afford 1.61 g of a brown crystalline solid (46%). 1H NMR (CDCl3) δ: 7.59-7.66 (m, 2H); 7.45-7.56 (m, 3H); 7.20 (s, 1H); 4.37 (d, J=12 Hz, 1H), 4.08 (d, J=12 Hz, 1H); 4.04 (s, 3H); 4.00 (s, 3H). MS (ES): m/z 365.0 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[CH3:38][N:37]1[C:33]([NH:32][C:19](=[O:21])[CH:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=3)=[CH:17][CH:16]=2)[CH3:22])=[CH:34][C:35]([CH3:39])=[N:36]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOc1ccc(C#Cc2ccc(C(C)C(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C#Cc2ccc(C(C)C(=O)Nc3cc(C)nn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 mg (0.11 mmol) 2-[4-(4-ethoxy-phenylethynyl)-phenyl]-propionic acid in (XI.2) 3 mL THF are added 55 μL (0.32 mmol) DIPEA, followed by 30 mg (0.11 mmol) chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate. The mixture is stirred at rt for 30 min. After that time, 12 mg (0.11 mmol) 5-amino-1,3-dimethylpyrazole are added and stirring is continued for 12 h. The solvent is removed and the residue is taken up in 1 mL DMF. 50 μL DIPEA are added, followed by 30 mg TBTU (0.11 mmol) and 12 mg (0.11 mmol) 5-amino-1,3-dimethylpyrazole. Stirring is continued for 12 h. The solvent is removed and the residue is purified by RP-HPLC (narrow gradients, water/ACN+0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:37][CH3:38])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([C:33]([O:35]C)=[O:34])[CH2:22]1.O.[OH-].[Li+].Cl>C1COCC1>[C:29]([O:28][C:26]([N:24]1[CH2:25][C@@H:21]([O:20][C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:37][CH3:38])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:12]3[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=3)[CH:8]=2)[CH2:22][C@H:23]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Temperature: 40 °C
Yield: 105.5 %

Procedure:
Compound 132 (20 g) was dissolved in THF (66 mL) at room temperature. Water (66 mL) was added, followed by lithium hydroxide (5 eq.) in one portion. The reaction mixture was heated at 40° C. for 3 hrs, cooled, acidified with 5M HCl, and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum to give compound 133 (20.57 g) as a yellow form in 99% yield and 96-97% purity.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]#[N:17])[C:12]([N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CCO.C(O)(=O)C>[NH2:18][C:12]1[C:13]([CH2:15][C:16]#[N:17])=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: N#CCc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCc1nc(OCc2ccccc2)ccc1N

Procedure:
11 g (40 mmol) (6-benzyloxy-3-nitro-pyridin-2-yl)-acetonitrile and 1.7 g Raney nickel (washed with abs. EtOH) in 120 mL EtOH and 50 mL acetic acid were hydrogenated at RT in a hydrogen atmosphere of 3 bar. The catalyst was filtered off and the filtrate was evaporated down. The residue was combined with 30 mL water and adjusted to pH=10 with solid sodium carbonate. The aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on magnesium sulphate, filtered and evaporated down. The residue was purified by flash chromatography. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]([C:10](C#N)=C)=[O:9].[C:14]1(C)C=CC=C[CH:15]=1>>[C:8]([O:7][C:6]1[CH:1]=[CH:2][C:3]([CH:14]=[CH2:15])=[CH:4][CH:5]=1)(=[O:9])[CH3:10]
Reactant: C=C(C#N)C(=O)OCCCCCC
Reactant: Cc1ccccc1
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
The purpose of this prophetic Example is to demonstrate the chemical derivatization of pHS in the organic extractant from the biphasic reaction medium to form the derivatized compound para-acetoxystyrene. The pHCA is first produced by fermentation using a recombinant strain of E. coli. The bio-produced pHCA is then converted to pHS in a biphasic reaction medium, consisting of fermentation supernatant and toluene, using PDC2 cell-free extract. After the toluene layer is separated from the pHCA-depleted fermentation supernatant, the bio-produced pHS is reacted with acetic anhydride to form para-acetoxystyrene.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5]O.[CH2:9]([N:11](CC)CC)C.CS(Cl)(=O)=O.CCCCC>CCOCC>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][C:9]#[N:11]
Reactant: OCCCC(F)(F)F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: N#CCCCC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 6.40 g (50.3 mM) 4,4,4-trifluorobutanol, prepared in Example 45d, and 7.71 ml (55.3 mM) triethylamine in 1.50 ml Et2O at 0° C. under N2, was added 4.28 ml (55.3 mM) methanesulfonyl chloride dropwise. A white precipitate formed and was stirred 60 minutes at 0° C. An equal volume of pentane was added and the reaction mixture was filtered through celite, followed by concentration on a rotary evaporator without heat. The crude mesylate was mixed with 8.19 g (126 mM) KCN and catalytic KI in 150 ml dimethysulfoxide at rt. The reaction mixture was then heated to 80° C. for 3 hours, turning deep orange and gelling. After cooling, the orange gel was poured into 100 ml of stirring H2O, extracted into Et2O, washed with saturated NaCl, dried over MgSO4, filtered and volatiles distilled. The crude liquid residue was 5.12 g (75%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([I:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=2)[CH:17]=[C:8]([C:6]2[C:5]([I:23])=[CH:4][C:3]([F:24])=[C:2]([NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[CH:7]=2)[C:9]1=[O:22])[CH3:21]
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2I)cc2cnc(NC)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2I)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
A suspension of 3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.310 g, 0.707 mmol) in DCM (10 mL) was treated with phenyl isocyanate (0.100 g, 0.839 mmol) followed by pyridine (0.060 g, 0.759 mmol) and stirred at RT for 3 h. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl)-3-phenylurea (120 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 7.05 (m, 2H), 6.24 (s, 1H), 4.14 (d, J=8.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 558.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(Cc3ccc(OC)c(OC)c3)CC2)cc1OC
Temperature: 97.5 °C
Reaction time: 8 h

Procedure:
3,4-dimethoxybenzyl chloride (10 g, 53.6 mmol) was combined with piperazine (2.3 g, 26.8 mmol) in anhydrous DMF (30 ml) and heated with stirring under nitrogen for 8 hours at 95-100° C. The cooled reaction mixture was diluted with water (100 ml) and acidified to pH 1 with concentrated hydrochloric acid. The white precipitate was collected by filtration and washed with water (50 ml). The solid was re-suspended in water (50 ml) and the pH adjusted to >9 by the dropwise addition of sodium hydroxide solution (50% NaOH in water). The resultant white solid was collected by filtration and dried under vacuum at 50° C., yield 10 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:9]=1[CH:10]=[O:11].[N+:18]([CH3:21])([O-:20])=[O:19]>C1COCC1>[Cl:7][C:8]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:9]=1[CH:10]([OH:11])[CH2:21][N+:18]([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
In a 3-necked 100 mL RBF, freshly ground potassium carbonate (0.486 g, 3.51 mmol) was added to a solution of 2,6-dichloro-3-fluorobenzaldehyde (2.26 g, 11.71 mmol) in THF (12 ml) at room temperature. Then nitromethane (8.88 ml, 164 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(2,6-dichloro-3-fluorophenyl)-2-nitroethanol (2.97 g, 11.69 mmol, 100% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.9, 4.8 Hz, 1H), 7.17 (dd, J=8.9, 7.8 Hz, 1H), 6.27 (m, 1H), 5.19 (dd, J=13.3, 10.1 Hz, 1H), 4.57 (dd, J=13.3, 3.4 Hz, 1H), 3.20 (br. s., 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH:17](O)[CH:18]([CH3:21])[CH2:19][CH3:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:21][CH:18]([C:17]1[NH:7][C:8]2[C:9]([CH:16]=1)=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:19][CH3:20]
Reactant: CCC(C)C(O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)c1cc2cc(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of tert-butyl[2-(2-hydroxy-3-methylpentyl)-4-methoxyphenyl]carbamate (2.65 g) in dichloromethane (25 mL) was added trifluoroacetic acid (5 mL) under ice-cooling. This mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Under an argon atmosphere, the residue was dissolved in N,N-dimethylformamide (30 mL), and then 2-bromomesitylene (1.50 mL), tetrakis(triphenylphosphine) palladium(0) (472 mg), and potassium carbonate (2.25 g) were added thereto. The mixture was stirred overnight at 150° C. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.46 g). 1H-NMR (CDCl3) δ ppm: 0.91 (3H, t, J=7.4 Hz), 1.32 (3H, d, J=7.0 Hz), 1.55-1.80 (2H, m), 2.75-2.90 (1H, m), 3.84 (3H, s), 6.15-6.20 (1H, m), 6.77 (1H, dd, J=2.4, 8.8 Hz), 7.02 (1H, d, J=2.4 Hz), 7.19 (1H, d, J=8.8 Hz), 7.77 (1H, br s).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(OC([N:31]1[CH2:35][C@H:34]([C:36]#[N:37])[CH2:33][C@H:32]1[C:38](=[O:40])[NH2:39])=O)(C)(C)C.CO>C(Cl)Cl>[C:36]([C@H:34]1[CH2:35][N:31]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:32]([C:38]([NH2:39])=[O:40])[CH2:33]1)#[N:37]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(N)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C[C@H](C#N)C[C@H]3C(N)=O)cc1OCC2
Yield: 72 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and (2S,4R)-2-carbamoyl-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester were reacted. The crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 430 as an off-white solid (41 mg, 72%). LCMS: RT=2.85 min, [M+H]+=435. 1H NMR 400 MHz (DMSO-d6) δ: 9.08 (1H, s), 7.88 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.56 (1H, br, s), 7.11 (1H, br, s), 6.04 (1H, s), 5.94-5.93 (1H, m), 4.51 (4H, d, J=15.42 Hz), 4.44 (1H, d, J=5.97 Hz), 3.92 (1H, dd, J=10.05, 7.55 Hz), 3.72 (1H, t, J=8.49 Hz), 3.61-3.53 (1H, m), 2.55-2.54 (1H, m), 2.35 (1H, ddd, J=12.61, 6.87, 3.63 Hz), 1.47 (6H, dd, J=6.59, 3.21 Hz)
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1.CCN(CC)CC>CN(C=O)C>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([S:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1ccc(S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Sc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.120 g, 0.40 mmol), methyl 2-(4-mercaptophenyl)acetate (0.100 g, 0.55 mmol), and Et3N (0.145 g, 1.3 mmol) in DMF was heated at 110° C. for 24 h. After this time, the mixture was concentrated, diluted with EtOAc (100 mL), washed with 10% aqueous LiCl (2×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 100% hexanes to 1:1 ethyl acetate/hexanes to afford the title compound (0.164 g, 100%) as a white solid. MW=409.93. 1H NMR (CDCl3, 300 MHz) δ 7.78-7.77 (m, 1H), 7.61-7.46 (m, 3H), 7.37 (d, J=8.2 Hz, 2H), 7.30-7.28 (m, 3H), 6.89 (s, 1H), 3.73 (s, 3H), 3.70 (s, 2H), 3.09 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.24-2.05 (m, 4H); APCI MS m/z 410 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:5]([O:6]1)[CH2:4][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]3)[CH:9]=1)[CH2:2]2.F[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:5]12[CH2:7][CH:1]([O:6]1)[CH2:2][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([NH:25][C:27]4[N:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:24]3)[CH:9]=1)[CH2:4]2
Reactant: NC1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Reactant: Fc1ncccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(NC2CCC(Oc3cc(N4CC5CC(C4)O5)cc4nccnc34)CC2)nc1
Temperature: 150 °C
Yield: 51.5 %

Procedure:
A mixture of 4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexanamine (190 mg, 0.5581 mmol), 2-fluoropyrimidine (60 mg, 0.6118 mmol) and DIEA (200 μL, 1.148 mmol) in 2-propanol (2 mL) was heated in a microwave reactor for 20 min at 150° C. The reaction mixture was concentrated, and then purified from 12 g silica gel cartridge with 0-6% MeOH/DCM to yield N-[4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexyl]pyrimidin-2-amine (120.2 mg, 48.9%) as a yellow solid. Mass+1: 419.23; Retention Time: 0.72; NMR Annotation: 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J=1.9 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.04 (d, J=4.8 Hz, 2H), 6.65-6.56 (m, 2H), 6.28 (t, J=4.8 Hz, 1H), 4.99 (d, J=8.1 Hz, 1H), 4.60 (d, J=6.5 Hz, 3H), 3.79 (dd, J=8.2, 4.0 Hz, 0H), 3.62-3.38 (m, 4H), 3.17-3.03 (m, 1H), 2.07-1.90 (m, 2H), 1.89-1.59 (m, 7H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH2:16]O)=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH2:16][Br:20])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Dissolve (4-benzyloxy-2,6-dichloro-phenyl)-methanol in 2.5 L THF and cool to 0° C. under N2. Add 94.45 g PBr3 dropwise and stir at 0° C. for 30 minutes. Pour the reaction mixture into sat'd. NaHCO3 and extract with EtOAc (2×). Dry over Na2SO4, filter and concentrate under vacuum to yield 269 g (89%) of the title compound as a white solid. MS (electrospray), 345.1, 347.1 (ES−).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH:13]([CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:30])([F:29])[F:18])=[CH:3][CH:4]=2)[CH2:8]1)([CH3:15])[CH3:14]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)C1CN(Cc2ccc(Br)cc2)CCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)C1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CCO1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 4-(4-Bromo-benzyl)-2-isopropyl-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture is filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.