Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[C:24]([C:25](Cl)=[O:26])=[C:23]([CH3:28])[O:22][N:21]=1>>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:25]([C:24]1[C:20]([C:14]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])=[N:21][O:22][C:23]=1[CH3:28])=[O:26]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)CCCCCN
Agent: Cl
Product: COC(=O)CCCCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 303.4 %

Procedure:
Methyl-6-aminohexanoate hydrochloride (349 mg, 1.92 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (527 mg, 1.92 mmol) were converted to 2.23 g of the title compound by the procedure of Preparation 10. (100%). EA calculated for: C18H20N2O4ClF: C, 56.48; H, 5.27; N, 7.32. Found: C, 56.66; H, 5.20; N, 7.07. MS(FD) m/z 382.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(Cl)c3ccc(Br)cc3c2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a screw cap pressure vessel, 7-bromo-4-chloroisoquinolin-1(2H)-one (Ark Chemicals, 2.50 g, 9.67 mmol) was added to a vial followed by cesium carbonate (6.30 g, 19.34 mmol) and DMF (9.67 mL). 1-(chloromethyl)-4-methoxybenzene (1.444 ml, 10.64 mmol) was added, the vial was capped and heated to 50° C. for 1 hours. The reaction was cooled to room temperature and water (20 mL) was added. The reaction was stirred for an additional 1 hour and filtered. The solid was collected and dried under a vacuum to yield 2.25 g of 7-bromo-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one as an off white solid. m/z (ESI) 380.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C@@:4]2([N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:18].C(C1C=CN=C(C2C=C(C(C)(C)C)C=CN=2)C=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1>O.C[OH2+].C[OH2+].C1CC=CCCC=C1.C1CC=CCCC=C1.[Ir].[Ir]>[F:52][C:49]1[CH:50]=[CH:51][C:46]([C:13]2[CH:12]=[C:11]([CH3:15])[N:10]=[C:9]([C:7]3[CH2:6][CH2:5][C@:4]4([CH2:16][CH2:17][N:2]([CH3:1])[C:3]4=[O:18])[N:8]=3)[CH:14]=2)=[CH:47][CH:48]=1
Reactant: Cc1cccc(C2=N[C@]3(CC2)CCN(C)C3=O)n1
Reactant: Fc1ccc(Br)cc1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(C)(C)c1ccnc(-c2cc(C(C)(C)C)ccn2)c1
Solvent: O
Solvent: C1=CCCC=CCC1
Product: Cc1cc(-c2ccc(F)cc2)cc(C2=N[C@]3(CC2)CCN(C)C3=O)n1
Temperature: 120 °C
Yield: 47 %

Procedure:
To a microwave vial was added (5R)-7-methyl-2-(6-methyl-2-pyridyl)-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 32) (100 mg, 0.4100 mmol), 4,4′-di-tert-butyl-2,2′-bipyridyl (11.03 mg, 0.0400 mmol), bis(pinocolato)-diboron (156.55 mg, 0.6200 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (13.62 mg, 0.0200 mmol). The microwave vial was sealed and evacuated and filled with nitrogen three times. 1,2-dimethoxyethane (2 mL) was then added and the reaction was heated in the microwave at 120° C. for 10 minutes. The vessel was cooled and a solution of sodium carbonate (217.81 mg, 2.06 mmol) in water (1 mL) was added, followed by 1-bromo-4-fluorobenzene (0.06 mL, 0.5100 mmol), and finally 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (16.82 mg, 0.0200 mmol). The reaction was then resealed, and heated in a microwave at 130° C. for 10 minutes. The cooled reaction mixture was partitioned between EtOAc (15 mL) and water (10 mL). The organics were separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was loaded onto silica (10 g SNAP column), and this was eluted with MeOH:EtOAc, 0% to 16%. Fractions containing desired product were combined and concentrated in vacuo to give (5R)-2-[4-(4-fluorophenyl)-6-methyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D33R) (65 mg, 0.1927 mmol, 46.9% yield) as a colourless oil;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(C(=O)N3CCOCC3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(C(=O)N3CCOCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: NC(=O)C1CC1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nccc2nc(-c3c(Cl)cccc3Cl)sc12)C1CC1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), cyclopropanecarboxamide (0.019 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (13 mg, 21% yield). 1H NMR (500 MHz, DMSO-d6): δ 11.44 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.72-7.67 (m, 3H), 2.09-2.06 (m, 1H), 0.9-0.87 (m, 4H). LCMS (Method A): RT=5.84 min, m/z: 371.0 [M+H+].
Reaction SMILES: C(NC1C=CC=CC=1)(OC(C)(C)C)=O.[H-].[Na+].BrCC(OCC(C)C)=O.[CH2:26]([O:30][C:31](=[O:49])[CH2:32][N:33](C(OC(C)(C)C)=O)[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=1)[CH:27]([CH3:29])[CH3:28]>C1COCC1>[CH2:26]([O:30][C:31](=[O:49])[CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)OC(=O)Nc1ccccc1
Agent: CC(C)COC(=O)CBr
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)COC(=O)CNc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichloroaniline (Aldrich) was treated with di-tert-butyl dicarbonate (Aldrich) using conventional procedures to produce the N-BOC aniline. The N-BOC aniline was treated with sodium hydride in THF and then with iso-butyl 2-bromoacetate (from Example AD above) to produce the N-BOC N-(3,4-dichlorophenyl)glycine iso-butyl ester. The BOC group was then removed using General Procedure AN above to afford the title compound. The reaction was monitored by tlc on silica gel (Rf=0.78 in 50% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 50% EtOAc/hexanes as the eluant).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[O:18]1CCOCC1.[OH-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.O>[OH:18][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: C1COCCO1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2c(C)c(C)c(C)c(C)c2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 76.3 %

Procedure:
A round-bottom flask was charged with N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (3.0058 g, 10.324 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.1843 g, 0.1780 mmol), and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-1-propylbiphenyl (0.2514 g, 0.5229 mmol). The flask was evacuated and backfilled with nitrogen five times and then 1,4-dioxane (10 mL, 200 mmol) and potassium hydroxide (2.413 g, 43.01 mmol) dissolved in water (10 mL, 800 mmol) were added. The reaction mixture was heated at 90° C. under a nitrogen balloon for 2 hours. The reaction mixture was then cooled to room temperature and poured into 150 mL water. The resulting precipitate was filtered, rinsed with water, and dried under vacuum to yield 1.7974 g (76%) of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): M+H=229.2; 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.90 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.27 (dd, J=8.9, 2.3 Hz, 1H), 7.22 (s, 1H), 2.13-1.95 (m, 1H), 0.91-0.70 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[CH:58][C:59]([C:62]([F:65])([F:63])[F:64])=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(C(F)(F)F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 101 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 110 mg colorless viscous oil (71%). MS (ISP) 479.5 (M+H)+.
Reaction SMILES: [Na].[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9].[H][H]>CO.[Ni]>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: O=C(O)C1CCC=CO1
Agent: [Ni]
Agent: [Na]
Solvent: CO
Product: O=C(O)C1CCCCO1

Procedure:
210 g. of the sodium salt of 3,4-dihydro-2H-pyran-2-carboxylic acid (5) was dissolved in 2 liters methanol and hydrogenated at 3 atm. pressure over 60 g. Raney nickel catalyst. After hydrogen uptake was complete, the catalyst was filtered and the solvents removed in vacuo. The residue was acidified with concentrated hydrochloric acid and extracted with chloroform. Distillation gave 143.8 g. product, b.p. 75° - 80° C./0.4 Mm, n25 = 1.4623.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(F)c2)cc1
Yield: 25.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-fluorophenyl)ethanol (prepared as described in Preparation 13), 3.44 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 60 ml of absolute methanol and 3.6 g of sodium cyanoborohydride, 1.18 g of the title compound were obtained as crystals, melting at 52° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:28]1[CH:29]=[C:30]([OH:38])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)([CH3:27])=[CH2:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:30]3[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:28]([C:25]([CH3:27])=[CH2:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: C=C(C)c1cc(O)cc(C(F)(F)F)c1
Product: C=C(C)c1cc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc(C(F)(F)F)c1
Yield: 84.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropenyl-5-trifluoromethyl-phenol (54 mg, 0.26 mmol) to give the title compound (60 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][C:9](=[O:36])[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11]1[S:12][C:13]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:14][C:15]=1[C:16]([O:18]CC)=O)(=O)C.IC>C(O)C>[CH3:5][N:8]1[C:16](=[O:18])[C:15]2[CH:14]=[C:13]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[S:12][C:11]=2[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:9]1=[O:36]
Reactant: CCOC(=O)c1cc(Cc2cccc3ccccc23)sc1N(CC(C)C)C(=O)NC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reaction time: 6 h

Procedure:
Sodium ethoxide (0.18 g) was added to a stirred solution of N′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(1-naphthalenylmethyl)-2-thienyl]urea (Example 3, step c), 0.30 g) in ethanol (6 ml). After 6 hours, iodomethane (0.165 ml) was added. After a further 16 hours iodomethane (0.165 ml) was added, After a further 24 hours, the reaction mixture was poured onto hydrochloric acid (2M, 30 ml) and extracted with ethyl acetate (2×30 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ether:hexane (1:1) and then triturated with ether to give the title compound (0.24 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:27]2[CH2:28][CH2:29][CH2:30][C@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:26]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N(CC#N)[C@H]1CCC[C@@H](Nc2nc(Cl)ncc2Cl)C1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@H](N(CC#N)S(C)(=O)=O)C4)n3)cc2CC1

Procedure:
rel-N-((1S,3R)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and rel-N-cyanomethyl-N-[(1S,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a tan foam (28 mg, 13%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.42 (d, 1H, J=8.0 Hz); 7.16 (s, 1H), 7.09 (d, 1H, J=8.1 Hz), 6.88 (s, 1H), 5.11 (d, 1H, J=7.2 Hz), 4.30-4.05 (m, 3H), 3.95-3.84 (m, 1H), 3.56 (t, 2H, J=5.8 Hz), 3.38 (s, 3H), 3.05-2.85 (m, 4H), 2.93 (s, 3H), 2.82-2.65 (m, 6H), 2.48-2.39 (m, 1H), 2.22-2.12 (m, 1H), 2.11-1.93 (m, 2H), 1.60-1.42 (m, 3H), 1.34-1.16 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 60 mg, 0.134 mmol), (6-methoxypyridin-3-yl)boronic acid (25.2 mg, 0.161 mmol), Pd2(dba)3 (2.463 mg, 2.69 μmol), 2-diclyclohexylphosphino-2′,4′,6′-triisoprophylbiphenyl (2.56 mg, 5.38 μmol) and K3PO4 (86 mg, 0.403 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and BuOH (269 μL) was added. The RM was stirred at 100° C. for 16 h, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, from 30% to 60% in 12 min.) to afford the title compound as a white solid. UPLC-MS (condition 1) tR=2.36 min, m/z=475.2 [M+H]+, m/z=473.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.78 (m, 1H) 1.77-1.90 (m, 1H) 2.93 (d, J=11.74 Hz, 1H) 3.18-3.26 (m, 2H) 3.35-3.46 (m, 1H) 3.91 (s, 3H) 4.20 (br. s, 1H) 4.83 (d, J=3.42 Hz, 1H) 6.91 (d, J=8.56 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.72 (dd, J=8.56, 2.45 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 7.97 (d, J=2.20 Hz, 1H) 8.21 (d, J=2.45 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)[CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:8]2[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=2)[CH2:7][CH2:6]1
Reactant: Nc1nnc(C2CC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclopropyl-2-amino-1,3,4-thiadiazole (6 grams) in ethyl acetate (100 ml) was added to the reaction vessel and the resulting mixture was stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was filtered to recover the desired product 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:15]2=[O:39])[CH2:10][CH2:9]1)=O)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=3)[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:39])=[CH:36][CH:35]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCNCC3)C2=O)cc1
Reaction time: 1.5 h

Procedure:
4-[3-(4-Methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.13 mmol) (from Example 2a supra) was dissolved at 0° C. in a 50% solution of trifluoroacetic acid in dichloromethane (6 mL) that contained 100 μL of water. After stirring for 1.5 hours the mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 by the addition of solid sodium hydroxide. The organic layer was then washed with water, dried over sodium sulfate, filtered and concentrated. The crude material was purified by precipitation out of tetrahydrofuran with excess of pentane to give 3-(4-methoxy-phenyl)-7-phenylamino-1-piperidin-4-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off white solid. (Yield 42 mg, 75%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[C:19]#[N:20].[OH:30][C:31]1[C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([N+:44]([O-:46])=[O:45])[CH:32]=1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C.O>[C:19]([C:18]1[C:17]([N+:22]([O-:24])=[O:23])=[CH:16][C:15]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:14]([CH:21]=1)[O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:30][C:31]1[C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([N+:44]([O-:46])=[O:45])[CH:32]=1)#[N:20]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCBr
Reactant: COCCOc1cc(C#N)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOC
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a solution of 5-(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)-2-nitrobenzonitrile (0.2 g) in DMF (8 mL) was added 4-hydroxy-5-(2-methoxyethoxy)-2-nitrobenzonitrile (0.1 g) and K2CO3 (0.5 g). The resulting mixture was heated at 80° C. overnight under N2 atmospheres. After reaction finished, the mixture was diluted with water (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.2 g of 4-(2-(2-(2-(2-(5-cyano-2-(2-methoxyethoxy)-4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)-2-nitrobenzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 7.92 (s, 1H), 7.84 (s, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 4.35-4.25 (m, 8H), 3.95-3.89 (m, 4H), 3.85-3.78 (m, 4H), 3.77-3.63 (m, 8H), 3.45 (s, 6H).