Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][NH:7][C:8](=O)[CH3:9].[CH3:11][S:12]([C:15]1[CH:46]=[CH:45][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:24](=[O:44])[N:25]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:26]([CH3:33])=[C:27]([C:29]([NH:31][NH2:32])=O)[CH:28]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:24](=[O:44])[N:25]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=3)[C:26]([CH3:33])=[C:27]([C:29]3[N:7]([CH3:6])[C:8]([CH3:9])=[N:32][N:31]=3)[CH:28]=2)=[O:22])=[CH:45][CH:46]=1)(=[O:14])=[O:13]
Reactant: Cc1c(C(=O)NN)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CNC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nnc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
A solution of POCl3 (0.030 g, 0.2 mmol) in CHCl3 (1 ml) and pyridine (1 ml) was added to N-methylacetamide (0.015 g, 0.2 mmol) and the mixture was cooled in an ice-water bath and stirred for 90 minutes. To this solution was added a solution of 5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (Example 38 (a), 0.040 g, 0.076 mmol) in CHCl3 (2 ml) and the mixture was stirred overnight at room temperature. Purification by preparative HPLC gave the linear intermediate (0.020 g). This material was suspended in EtOAc (2 ml) and was heated (90° C.) with stirring for 4 h, giving rise to a mixture of three components. This mixture was purified on preparative HPLC giving the title compound (0.003 g, 7%) after freeze-drying the pure fractions.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:25]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[C:25]([C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (37.5 mL, 487 mmol) was added rapidly dropwise to a stirred solution of 3a (8.62 g, 19.5 mmol) in DCM (100 mL) at 0° C. After 1 h, the reaction was quenched by careful addition of saturated aqueous sodium bicarbonate, followed by NaHCO3(s) and extracted with ether. The organics were washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound 3b. m/z (ES) 343 (MH)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][Si](C(C)(C)C)(C)C)[CH:12]=O)(C(C)(C)C)(C)C.O[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1O)[CH:29]=[O:30].[C:35]([Si](C)(C)Cl)(C)([CH3:37])[CH3:36].N1C=CN=C1>>[OH:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:36]\[CH2:35][CH2:37][CH2:31][CH2:32][CH2:33][CH2:26][C:27]#[C:28][CH2:29][OH:30])[CH:14]=[CH:15][C:16]=1[OH:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1ccc(O)c(O)c1
Agent: c1c[nH]cn1
Product: OCC#CCCCCCC/C=C\c1ccc(O)c(O)c1

Procedure:
The 3,4-bis-(tert-butyldimethylsilyloxy)-benzaldehyde used in Example 23d as one of the starting materials was prepared by reacting 2.14 g of 3,4-dihydroxybenzaldehyde, 5.83 g of tert-butyldimethylchlorosilane and 2.58 g of imidazole in the manner described in Example 14c. Chromatography with petroleum ether/ether (6:1) yielded 3.57 g of the title compound in the form of crystals melting at 44°-46° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)[CH2:6][C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc2[nH]ncc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)O)Nc1ccc2[nH]ncc2c1

Procedure:
A stirred solution of 2-(1H-indazol-5-ylamino)-succinic acid 4-tert-butyl ester 1-ethyl ester (123.6 mg, 0.37 mmol) in methylene chloride (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and washed with saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to give a dark green oil: LC/MS: tR=0.643 min, 278.19 (MH)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:29]1([CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([N:39]3[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:41][CH2:40]3)=[O:26])[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: C1CCN(CCC2CCNCC2)C1
Reactant: CCOC(=O)c1nc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2noc(C(=O)N3CCC(CCN4CCCC4)CC3)n2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.07 mmol), 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (29 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:21])[CH:10]=[C:11]([CH2:16][CH2:17][C:18](O)=[O:19])[C:12]=2[O:14][CH3:15])[N:7]([CH2:22][CH3:23])[CH:6]=1.C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C1COCC1.O>[CH3:1][N:2]([CH3:25])[C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:21])[CH:10]=[C:11]([CH2:16][CH2:17][C:18]([NH2:27])=[O:19])[C:12]=2[O:14][CH3:15])[N:7]([CH2:22][CH3:23])[CH:6]=1
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)O)cc(F)c21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(N)=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of 28-2 (180 mg, 0.51 mmol), HATU (388 mg, 1.02 mmol), DIPEA (220 mg, 1.7 mmol) and ammonium chloride (73 mg, 1.36 mmol) in THF (10 mL) was stirred at room temperature overnight. Water (10 mL) was added, and the reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over MgSO4, filtered and evaporated to give crude product, which was purified by preparative TLC (petroleum ether/ethyl acetate=1:1) to afford 28-3 (150 mg, 84%) as a yellow solid. LRMS: calc 349.2 and found: 350.0 [M+1].
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][CH:25]=1.[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:49]([C:50]2[NH:51][CH:52]=[CH:53][N:54]=2)=[CH:48][N:47]=[C:46]([NH:55][CH2:56][CH2:57][NH:58]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:45]=1>>[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:49]([C:50]2[NH:54][CH:53]=[CH:52][N:51]=2)=[CH:48][N:47]=[C:46]([NH:55][CH2:56][CH2:57][NH:58][C:24]2[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][CH:25]=2)[N:45]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CN(C)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)c1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)-amino]-3-nitro(2-pyridyl)}dimethylamine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-dimethylamino-3-nitro pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))-amino]ethyl}amine.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 91 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 91% of theory, C25H25N7O3 (471.5); EKA mass spectrum: (M+H)+=472; (M+H+Na)++=247.6; (M+2H)++=236.7; (M+2Na)++=258.6.
Reaction SMILES: FC(F)(F)C1C=CC(N2C3C(=CC=CC=3)C([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=N2)=CC=1.C1([N:32]=[C:33]=[O:34])C=CC=CC=1>C1(C)C=CC=CC=1>[N:21]1([C:33]([NH2:32])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]1
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)N1CCCCC1

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 77 (15 g 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene (60 ml) was added phenyl isocyanate (1.38 ml, 0.013 moles). The reaction temperature rose to 35° C. and the product precipitated from the solution. The product was collected and recrystallized twice from toluene to yield 3.57 g (66%) of N-phenyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p. 190°-192 ° C.
Reaction SMILES: ClC[C:3]([NH2:5])=O.[CH3:6][NH:7][C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.O1CCC[CH2:19]1>>[C:10]1([CH:9]2[NH:5][CH2:3][CH2:6][N:7]([CH3:19])[CH2:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)CCl
Reactant: CNC(=O)Cc1ccccc1
Reactant: C1CCOC1
Agent: Cl
Product: CN1CCNC(c2ccccc2)C1
Yield: 81.97 %

Procedure:
Compound (I) of the previous example (0.5 g, 2.077 mmol) and tetrahydrofurane (5 mL) were placed in a 25 mL flask, and for approximately 10 minutes the BH3.THF complex 1 M (10.4 mL, 10.386 mmol) was added to the white suspension. The resulting colourless solution was heated to reflux temperature for 6.5 hours, it was cooled to 19°±1° C. and an aqueous solution of HCl 6 N (1.82 mL) was added slowly. The mixture was distilled at reduced pressure to remove the tetrahydrofurane. Ethyl acetate (5 mL) was added and was extracted with an aqueous solution of HCl 2 N (3×5 mL). The accumulated acidic phases were alkalinised with an aqueous solution of NaOH 50% (p/p) to pH 12-13 (1.1 mL), saturated with NaCl (6.25 g) and were extracted with ethyl acetate (3×5 mL). The accumulated organic phases were dried with anhydrous Na2SO4, they were filtered and evaporated at reduced pressure, giving a yellowish liquid residue which corresponded to the title product (0.3 g, 81.97%).
Reaction SMILES: [C:1]([O:4]/[N:5]=[C:6](\[NH2:24])/[CH2:7][C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:18]1([C:8]2([CH2:7][C:6]([NH2:24])=[NH:5])[CH2:9][CH2:10][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:16][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O/N=C(\N)CC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: CC(=O)O
Product: N=C(N)CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a stirred solution of (Z)-(1-amino-2-{8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl}ethylidene)amino acetate (267) (1.4 g, 4.21 mmol) in methanol was added Pd—C (10%) under nitrogen atmosphere and the mixture was kept under a hydrogen atmosphere of balloon pressure at room temperature for 2 h (reaction was monitored by LC-MS). The reaction mixture was filtered and the filtrate was concentrated in vacuo to get a sticky mass which was triturated with diethyl ether to get pure 2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)acetamidine acetic acid salt (268) (1.25 g, 88.79%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1([O:15][CH2:14]1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:11][C:12]([CH3:14])([OH:15])[CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: CC1(C)CO1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Yield: 103 %

Procedure:
4-Bromo-3,5-dimethylphenol (4.0 g), isobutylene oxide (2.0 g) and Cs2CO3 (9.7 g) in N,N-dimethylformamide (10 mL) are stirred at 100° C. for 20 h. After cooling the mixture is partitioned between water and EtOAc, the organic layer dried (MgSO4) and concentrated. Purification of the residue by column chromatography (silica gel, n-hexane:EtOAc 100:0 to 50:50 gradient) gives the desired compound (5.6 g, content ca. 97%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][C:15]([CH2:19][CH3:20])([OH:18])[CH2:14][CH2:13]1)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][C:15]([CH2:19][CH3:20])([OH:18])[CH2:14][CH2:13]1
Reactant: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC1(O)CCC(CN)CC1

Procedure:
A mixture of EXAMPLE 358A (500 mg) and 10% Pd/C (100 mg) in tetrahydrofuran (15 mL) was stirred under H2 for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5]CC)=O.[CH3:11][O-].[Na+].CO.[CH3:16][NH:17][CH3:18]>>[OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([N:17]([CH3:18])[CH3:16])=[O:5]
Reactant: C[O-]
Reactant: CNC
Reactant: CCCC(O)C(=O)OCC
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)C(=O)N(C)C
Yield: 80 %

Procedure:
In a three-neck flask, at 20° C. and under an inert atmosphere, are mixed ethyl 2-hydroxyvalerate (31 g; 210 mmol) and sodium methylate in solution in methanol (25% w/w) (2.2 g; 10 mmol). To this mixture, is added dimethylamine in solution in methanol (50% w/w) (37.1 g; 411 mmol) within 30 minutes. The temperature of this mixture is brought to 40° C. and maintained for 3 hours. After return of the temperature of the reaction mixture to 20° C., orthophosphonic acid is added until a pH of 5 is obtained. The salts formed are removed by filtration and the solvents are removed under reduced pressure. 2-hydroxy-N,N-dimethylhexanamide is then obtained with a purity <98% i.e. a yield of 80%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[O:20][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:23]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.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>[CH3:18][C:19]1[O:20][C:21]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:22][N:23]=1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)o1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
A mixture of Example A1 (600 mg, 2.38 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (648 mg, 3.10 mmol), K2CO3 (989 mg, 7.15 mmol) and Pd(PPh3)4 (138 mg, 0.119 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. overnight. Additional 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (100 mg) and Pd(PPh3)4 (50 mg) were added, the mixture heated at 80° C. for 5 h, then cooled to RT and treated with water and EtOAc. The solids were removed via filtration through diatomaceous earth, the layers of the filtrate separated and the organic layer was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (323 mg, 45%). MS (ESI) m/z: 299.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:9]1[C:10]([NH:12][CH:13]1[CH:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:15](=[O:26])[CH2:14]1)=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:9]1[C:10]([NH:12][CH:13]1[CH:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:16][C:15](=[O:26])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(NC(=O)C2CCCCN2)C(OCc2ccccc2)O1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
N-(N-tert-Butoxycarbonylpipecolyl)-4-amino-5-benzyloxy-2-oxo-tetrahydrofuran (654 mg) was dissolved in 15 ml of 25% trifluoroacetic acid in dichloromethane and stirred at room temperature. The mixture was concentrated to give a gummy residue. The residue was dissolved in dichloromethane and washed with 10% sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 422 mg of the title compound as a beige solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[CH3:11][NH2:12]>C1COCC1.CCN(C(C)C)C(C)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][CH3:11])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
Cyanuric chloride (10 g, 54.3 mmol, 1 equiv.) was dissolved in THF (200 mL) and cooled to −70° C. DIPEA (36.3 mL, 1.42 mmol, 2 equiv.) and methylamine hydrochloride (3.7 g, 1 equiv.) were added to the reaction mixture, which was stirred 2 h at −70° C. and 1 h at rt. The THF was removed under reduced pressure and the remaining material was taken up in DCM and washed with water. The organic layer was dried with MgSO4 and the DCM removed to give a colourless powder (9.5 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][CH2:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: NCc1ccncc1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccncc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 4-(aminomethyl)pyridine (47.5 mg, 0.439 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=432 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][C:30](=[O:36])[N:29]([CH2:37][CH3:38])[C:28]=2[CH:39]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][C:30](=[O:36])[N:29]([CH2:37][CH3:38])[C:28]=3[CH:39]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4N(C)CCC#N)n3)cc21

Procedure:
Title compound was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound isolated as a white lyophilate (82 mg, 61%). HPLC 99% purity, LCMS 538.20 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.10 (s, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 7.38-7.32 (m, 1H), 7.21 (m, 2H), 6.99-6.92 (m, 2H), 3.70-3.60 (m, 2H), 3.26 (t, J=6.5 Hz, 2H), 2.69 (s, 3H), 2.52 (t, J=6.4 Hz, 2H), 2.24-2.20 (m, 2H), 2.10-1.98 (m, 2H), 1.32 (s, 6H), 1.09 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O)(=O)C.[F-].P([O-])(O)(O)=O.[K+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[S:9][C@@H:8]([CH2:10][OH:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: O=P([O-])(O)O
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC1CC[C@H](CO)S1
Reaction time: 5 h
Yield: 71.5 %

Procedure:
To a mixture of 0.54 g of 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4thioribofuranose (prepared by the procedure of J. A. Secrist et al., J. Med. Chem.,1992, 35, 533) in 8 ml of tetrahydrofuran and 0.6 g of acetic acid is added 4 mmol of 1M n-tetrabutylamnonium fluoride solution. The reaction is stirred for 5 hours and then another portion of 0.10 g of acetic acid and 1 mmol of n-tetrabutylammonium fluoride is added and the reaction is stirred for 1 hour. Cold potassium dihydrogen phosphate and ethyl acetate are added to the reaction mixture, followed by an aqueous workup. Purification by chromatography gives 0.164 g of the desired product.