Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:26]=[CH:25][C:11]([CH:12]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[NH:36][C:37](=[O:40])[CH2:38]Cl.C(OCC)(=O)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:38][C:37](=[O:40])[NH:36][C:29]3[C:28]([CH3:27])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])[CH2:23][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(NC(=O)CN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 7.5 h

Procedure:
2 g of anhydrous potassium carbonate were added to a mixture of 192.6 mg of 1-(4-chlorobenzhydryl)piperazine and 142.7 mg of N-(2,4,6-trimethylphenyl)chloroacetamide dissolved in 20 ml of N,N-dimethylformamide, and the reaction mixture was stirred at 80° C. for 7.5 hours. At the end of this time, ethyl acetate was added to the mixture, and the organic layer was separated. The organic layer was washed three times with water, and then the solvent was evaporated off under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford a purified 1-(4-chlorobenzhydryl)-4-(2,4,6-trimethylphenylcarbamoylmethyl)piperazine.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O.[CH3:44][NH:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][CH2:52][C:53]([F:59])([F:58])[C:54]([F:57])([F:56])[F:55].O>CN(C=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:9]=[CH:8][C:7]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[CH:6][C:5]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:45]([CH3:44])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][CH2:52][C:53]([F:59])([F:58])[C:54]([F:55])([F:56])[F:57]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OC4CCCCO4)ccc3[C@@H]3[C@@H]2[C@@H]2CCC(=O)[C@@]2(C)C[C@@H]3F)cc1
Reactant: CNCCCSCCCC(F)(F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCSCCCC(F)(F)C(F)(F)F
Reaction time: 6.5 h

Procedure:
2.0 g of 11β-fluoro-3-(tetrahydropyran-2-yloxy)-7α-(5-p-toluenesulphonyloxypentyl)oestra-1,3,5(10)-trien-17-one in 44 ml of DMF are stirred at 80° C. with 1.2 g of methyl-[3-(4,4,5,5,5-pentafluoropentylthio)propyl]-amine. After 6.5 h, the reaction mixture is treated with water. The mixture is extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. After chromatographing the crude product on silica gel using a methylene chloride-methanol gradient, 1.3 g of 11-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]-pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one are obtained as an oil.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][P:4]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)([O:5][CH2:6][CH3:7])=[O:3])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
Triethylphosphite (9.28 mL, 53.3 mmol) and α-bromo-p-toluic acid (10.4 g, 48.4 mmol) were suspended in toluene (25 mL) and the mixture was heated to reflux for 18 h. The mixture was cooled to room temperature. After 12 h, the resulting white solid was collected by suction filtration, washed with petroleum ether and dried to yield 4-(diethoxyphosphorylmethyl)benzoic acid as a white solid (10.2 g, 77%): mp 117-120° C.; 1H NMR δ 1.26 (t, J=6.8 Hz, 6H), 3.24 (d, J=25.6 Hz, 2H), 4.06 (m, 4H), 7.38-7.40 (m, 2H), 8.02 (d, J=7.6 Hz, 2H), 11.4 (br s, 1H); 13C NMR δ 16.5, 16.6, 33.4, 34.8, 62.8, 62.9, 129.1, 129.2, 130.00, 130.05, 130.10, 130.48, 130.51, 137.3, 137.4, 170.1; FABMS obsd 273.0896, calcd 273.0892; Anal. Calcd. for C12H17O5P: C, 52.94; H, 6.29; Found: C, 52.92; H, 6.28. A suspension of 4-(diethoxyphosphorylmethyl)benzoic acid (9.99 g, 36.7 mmol) in anhydrous THF (40 mL) at 0° C. was treated dropwise over 10 min with borane-THF complex (40.3 mL, 40.3 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by slow addition of water. The mixture was concentrated and the residue was partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Analysis by TLC and 1H NMR spectroscopy showed starting material (˜10%) and the desired benzyl alcohol. The latter (9.56 g) was dissolved in CH2Cl2 and rapidly added to a sample of PCC (10.8 g, 50.1 mmol) in CH2Cl2 (50 mL) with rapid stirring. After 2 h, ethyl ether (150 mL) was added and the organic solution was decanted from the tarry residue. The residue was washed with ethyl ether (3×50 mL). The combined organic solution was filtered through Florisil and concentrated to a brown oil. Kugelrohr distillation (190° C. @0.05 Torr) afforded a clear, colorless oil (6.54 g, 77%): 1H NMR δ 1.24 (t, J=7.2 Hz, 6H), 3.21 (d, J=22.4 Hz, 2H), 4.03 (m, 4H), 7.45-7.48 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 9.99 (s, 1H); 13C NMR δ 16.1, 16.2, 33.0, 34.9, 62.1, 62.2, 77.2, 129.49, 129.53, 129.6, 129.66, 129.71, 130.2, 130.2, 138.8, 138.9, 191.61, 191.63; 31P NMR δ 25.4, 25.9; FABMS obsd 257.0949, calcd 257.0943 (C12H17PO4).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18](=[O:20])[NH2:19])=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([O:24][CH:11]([C:10]1[CH:9]=[CH:15][CH:14]=[C:13]([O:16][CH2:17][C:18](=[O:20])[NH2:19])[CH:12]=1)[C:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:23])[CH3:22]
Reactant: NC(=O)COc1ccc2oc(-c3ccccc3)cc2c1
Reactant: CC(=O)O
Product: CC(=O)OC(C(=O)c1ccccc1)c1cccc(OCC(N)=O)c1

Procedure:
Irradiation of 7 resulted in a clean conversion to the phenylbenzofurans 8 and 9. Steady-state photolysis spectra of 7 show two isosbestic points throughout the course of the photolysis (FIG. 3). The two isomeric photoproducts 8 and 9 were produced in a 98% yield at a ratio of 3:1 as determined by GCMS and NMR of the isolated phenylbenzofurans, along with an equivalent of acetic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([N:18]2[CH2:17][CH2:16][O:15][CH2:20][CH2:19]2)=[N:22][CH:23]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(N2CCOCC2)nc1
Yield: 56.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.042 g, 0.178 mmol), 6-morpholinonicotinoyl chloride (0.045 g; 0.178 mmol), and triethylamine (0.062 mL; 0.446 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) furnished 0.039 g (57%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide as a solid.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[O:14][C:11]2[CH:12]=[C:13]3[C:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=2)=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF; 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-chlorophenyl isocyanate (411 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 32 hours under N2 atmosphere at RT (35° C.). The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to afford 10f as solid. Yield: 520 mg, 71.42%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Br.Br.Br[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:25][C:26]2[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(Cc2cnc(N)nc2N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A solution of 3.2 g (0.017 mol) of 1-(2-methoxy-phenyl)-piperazine in 100 ml of tetrahydrofuran was treated with 11.6 ml (0.084 mol) of triethylamine and 6.1 g (0.017 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 2.0 g (38%) of 5-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as white crystals; m.p. 195°-196°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]([NH2:37])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35]([NH2:37])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: NC(=O)CS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: NC(=O)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)acetamide. MS (ESI): mass calcd. for C18H15FN4O3S, 386.41; m/z found, 387.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=1.4, 2H), 8.15 (dd, J=7.9, 1.2, 1H), 7.80-7.72 (m, 1H), 7.69-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.43 (dd, J=7.5, 1.3, 1H), 7.39-7.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[CH:4][N:3]=1.C([Li])CCC.CON(C)[C:18](=[O:33])[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:18](=[O:33])[CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Reactant: Fc1cnc(Cl)cc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(c1ccccc1)c1ccccc1)c1cc(Cl)ncc1F
Reaction time: 1 h

Procedure:
At −70° C. to a solution of 2-chloro-5-fluoro-4-iodopyridine (873 mg) in THF (20 mL) was added n-butyllithium (2.2 mL, 1.6M in hexane) over a period of 15 min slowly. To that solution N-methoxy-N-methyl-3,3-diphenyl-propionamide (200 mg) in THF (8 mL) was added and stirring was continued at that temperature for 1 h. A saturated solution of NH4Cl was added, the mixture was diluted with EtOAc, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/n-heptane 1:2) to yield the title compound as a white solid, MS (ESI+): m/z=340.09 ([M+H]+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=[O:35])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:74][C:75]([CH3:79])([CH3:78])[CH2:76]N>C(Cl)Cl>[OH:74][C:75]([CH3:79])([CH3:78])[CH2:76][O:35][C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])[CH:32]=1
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OCC(C)(C)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA (0.41 mmol) and 2-hydroxy-2-methyl-propylamine (Matrix, 24 mg, 027 mmol). The mixture was stirred at rt 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 75 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Br[CH2:14][CH2:15][OH:16]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Temperature: 60 °C

Procedure:
To a solution of 3-nitrophenol (10 g, 71.9 mmol) in DMF (40 ml) was added NaOH pellets (3.16 g, 79.1 mmol) and 2-bromoethanol (5.6 ml, 79.1 mmol). The reaction mixture was heated at 60° C. for 18 h. LCMS indicated 65% conversion to the required product. The reaction mixture was diluted with water (10 ml) and was slowly neutralised with 2M HCl. The reaction mixture was extracted with EtOAc (50 ml) and washed with water (50 ml). The EtOAc layer dried (Na2SO4), filtered and evaporated to dryness. Flash column chromatography purification eluting with 30% EtOAc/heptane gave the required product (8.2 g, 62% yield). LCMS purity 100%, m/z 184 [M+H]+.
Reaction SMILES: [O-][N+:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]3[CH2:12][C@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][N:8]3[C:4]=2[CH:3]=1.O(Cl)[Cl:33].[P+3]>C(Cl)(Cl)Cl>[Cl:33][C:3]1[C:4]2[N:8]3[CH2:9][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[CH2:12][C:7]3=[N:6][C:5]=2[CH:30]=[CH:31][N:2]=1
Reactant: ClOCl
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc[n+]([O-])cc32)C[C@@H]1c1cc(F)c(F)cc1F
Agent: [P+3]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3ccnc(Cl)c32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C

Procedure:
To the product of Step A in 1.5 mL of chloroform was added 0.008 mL (0.09 mmol) of phosphorus(III) oxychloride and the resultant mixture was refluxed for 1.5 h. The reaction mixture was cooled to ambient temperature, diluted with chloroform (10 mL), and sequentially washed with saturated aqueous sodium bicarbonate solution (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by preparative thin layer chromatography using an Analtech® 1000 micron plate (4% methanol/ethyl acetate) to give the title compound as a viscous oil. LC/MS 453.0 (M+1), 454.8 (M+2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23]2[C:24](=O)[CH2:25][CH2:26][C:27]=2[CH:28]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl>[Cl:19][C:20]1[CH:28]=[C:27]2[CH2:26][CH2:25][CH:24]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]4([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]4)[CH:7]=3)[C:23]2=[N:22][CH:21]=1
Reactant: O=C1CCc2cc(Cl)cnc21
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)N=C(N)COC[C@@H]1F
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20 mg, 78.4 μmol) in 1,2-dichloroethane (200 μl) was added at 23° C. under inert atmosphere 3-chloro-5,6-dihydro-[1]pyrindin-7-one (14.4 mg, 86.2 μmol) and acetic acid (9.41 mg, 8.97 μl, 157 μmol) and the solution was stirred at 23° C. for 30 min. Then sodium triacetoxyborohydride (24.9 mg, 118 μmol) was added and the mixture was stirred at 23° C. for 4 h. After addition of 1 M HCl (1 ml) and stirring for 10 min, the aqueous layer was washed once with dichloromethane, then treated with sat. Na2CO3-sol. to achieve pH 14 and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to give a crude product, which was purified by basic preparative HPLC to give (5R,6R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (11 mg, 27.0 μmol, 34.5% yield) as a colorless oil. MS (ISP): m/z=407.3.3 [(M+H)+] and 409.3 [(M+2+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([F:30])[CH:32]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C(O)c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3cccc(F)c3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (75% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 23 mg (0.17 mmol, 1.1 eq.) of 3-fluorobenzoic acid were reacted according to General Method 1. Yield: 41 mg (65% of theory)
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:21](=[O:22])[CH2:20][NH:19][CH2:18][C:17]1=[O:23].[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>N1C=CC=CC=1.C(Cl)Cl>[CH2:26]([S:30]([N:19]1[CH2:18][C:17](=[O:23])[N:16]([CH2:15][C:5]2[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:8]3[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=3[CH:6]=2)[C:21](=[O:22])[CH2:20]1)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)Cn1c(CN2C(=O)CNCC2=O)cc2cnc(C#N)nc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N1CC(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 200 mg (0.59 mmoles) of 7-(2,2-dimethyl-propyl)-6-(2,6-dioxo-piperazin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 4 ml of pyridine, 184 mg (1.2 mmoles) of 1-butanesulfonylchloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 2 hours and the mixture is concentrated under reduced pressure. The obtained crude powder is dissolved in CH2Cl2, and the CH7Cl2 layer is washed with 1N aqueous HCl, brine, and then dried over MgSO4. The CH2Cl2 layer is concentrated under reduced pressure to give colorless powder, which is washed with ether to give 195 mg of desred 6-[4-(Butane-1-sulfonyl)-2,6-dioxo-piperazin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 72% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH:10]4[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH2:15]4)[CH2:3][CH2:2]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: OCCN1CCC(CCCC2CCNCC2)CC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CCCC2CCN(CCO)CC2)CC1

Procedure:
The title product was prepared from 2-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanol and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate. The reaction mixture was evaporated, diethyl ether (30 ml) was added and the title product isolated by filtration, washed with diethyl ether and dried to give (67%, white solid. HPLC-MS m/z=(M+1) 536.2, Rt: 3.39 min.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]([NH2:25])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[C:24]([N:25]3[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]3)=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: CN(CCCl)CCCl
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2c[nH]nc2C(=O)Nc2ccc(F)cc2)CC1
Temperature: 200 °C
Yield: 19.8 %

Procedure:
Bis(2-chloroethyl)methylamine hydrochloride (97 mg; 0.5 mmol) was added to a stirred solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (100 mg; 0.45 mmol), tetrabutylammonium iodide (20 mg; 0.045 mmol) and diisopropyethylamine (200 ul) 1.13 mmol) in DMF (5 ml), and the resulting mixture was heated at 200° C. (100 W) for 30 minutes in a CEM Discover™ microwave synthesiser. The DMF was removed under vacuum, then purified by flash column chromatography, eluting with dichloromethane/methanol/acetic acid/water (90:18:3:2). Product containing fractions were combined and evaporated, treated with HCl in ethyl acetate and then re-evaporated with toluene (2×20 ml) to give an off white solid (27 mg). (LC/MS: Rt 1.64, [M+H]+ 378).