Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCN(C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3C(F)(F)F)=O)=CN=2)CC1)=O)(C)(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][C@H:47]([NH:50][C:51]2[N:56]=[CH:55][C:54]([NH:57][C:58]([C:60]3[N:61]=[C:62]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=4[O:75][C:76]([F:79])([F:78])[F:77])[O:63][C:64]=3[C:65]([F:68])([F:67])[F:66])=[O:59])=[CH:53][N:52]=2)[CH2:46]1)=[O:44])(C)(C)[CH3:39].FC(F)(F)OC1C=CC=CC=1C1OC(C(F)(F)F)=C(C(O)=O)N=1.C(OC(N1CC[C@H](NC2N=CC(N)=CN=2)C1)=O)C>>[CH2:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][C@H:47]([NH:50][C:51]2[N:52]=[CH:53][C:54]([NH:57][C:58]([C:60]3[N:61]=[C:62]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=4[O:75][C:76]([F:79])([F:78])[F:77])[O:63][C:64]=3[C:65]([F:66])([F:67])[F:68])=[O:59])=[CH:55][N:56]=2)[CH2:46]1)=[O:44])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncc(NC(=O)c3nc(-c4ccccc4OC(F)(F)F)oc3C(F)(F)F)cn2)C1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Agent: CCOC(=O)N1CC[C@H](Nc2ncc(N)cn2)C1
Agent: O=C(O)c1nc(-c2ccccc2OC(F)(F)F)oc1C(F)(F)F
Product: CCOC(=O)N1CC[C@H](Nc2ncc(NC(=O)c3nc(-c4ccccc4OC(F)(F)F)oc3C(F)(F)F)cn2)C1

Procedure:
With a method similar to that used for the preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester above, (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(5-amino-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C23H20F6N6O5 (m/e) 574.4, obsd 575.2 (M+H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(OC(=O)C)(=O)C.[N+:13]([CH2:16][CH2:17]O)([O-:15])=[O:14]>C(OCC)(=O)C.[Cl-].[Na+].O>[N+:13]([CH2:16][CH2:17][O:3][C:1](=[O:4])[CH3:2])([O-:15])=[O:14]
Reactant: O=[N+]([O-])CCO
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCC[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1.17 h
Yield: 366 %

Procedure:
A mixture of sodium acetate (6.4 g, 78 mmol) and acetic anhydride (30 mL, 330 mmol) was stirred at 0-5° C. To this slurry was added 2-nitroethanol (30 g, 280 mmol) dropwise over a period of approximately 1 hour. After the 2-nitroethanol addition, the orange reaction mixture was stirred at 0-5° C. for an additional hour and then at ambient temperature for approximately 70 min, the exotherm of the reaction increased the temperature to 30° C. and the mixture was cooled with an ice bath to 20° C. The reaction was then stirred at ambient temperature under N2 overnight. The reaction mixture was diluted with ethyl acetate (EtOAc, 40 mL) and saturated brine (80 mL). The layers were separated and the bottom aqueous layer was extracted again with ethyl acetate (25 mL). The combined ethyl acetate layers were washed once with saturated brine (50 mL), dried (MgSO4), filtered and concentrated to afford 38 g of 2-nitroethylacetate as a reddish orange oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][S:6][C@H:5]2[CH2:9][CH2:10][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:12][N:4]2[C:3]1=[O:17].O=C1[C@@H](NC(=O)OCC2C=CC=CC=2)CCS[C@H]2CC[C@@H](C(F)(F)F)CN12>>[NH2:1][C@H:2]1[CH2:8][CH2:7][S:6][C@H:5]2[CH2:9][CH2:10][C@@H:11]([C:13]([F:15])([F:14])[F:16])[CH2:12][N:4]2[C:3]1=[O:17]
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Agent: O=C(N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O)OCc1ccccc1
Product: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O

Procedure:
(4S,8R,10aS)-4-Amino-8-(trifluoromethyl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one (50 mg, 0.19 mmol) was synthesized as described for the preparation of Intermediate 60 using benzyl (4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate. Anal. Calcd. for C10H15F3N2OS m/z 268.2. found: 269.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 5.30 (dd, J=5.3, 3.8 Hz, 1H), 4.60 (dd, J=13.4, 4.3 Hz, 1H), 4.06 (dd, J=10.0, 4.2 Hz, 1H), 3.04 (ddd, J=14.3, 9.9, 3.0 Hz, 1H), 2.91 (t, J=12.8 Hz, 1H), 2.66 (ddd, J=14.6, 7.2, 3.1 Hz, 1H), 2.39-2.16 (m, 2H), 2.05 (dddd, J=14.5, 9.7, 7.8, 4.1 Hz, 2H), 1.94-1.85 (m, 1H), 1.80-1.64 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[N:21][OH:22])[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4.0 g of 4-acetyl-piperidine-1-carboxylic acid benzyl ester, 25 mL of pyridine, and 6 g of hydroxylamine hydrochloride were heated to 100° C. for 12 h. The mixture was concentrated under reduced pressure and partitioned between 200 mL of ethyl acetate and 50 mL of 1N HCl. The organic extract was dried over magnesium sulfate and concentrated to dryness under reduced pressure. Drying under vacuum gave 4-(1-hydroxyimino-ethyl)-piperidine-1-carboxylic acid benzyl ester as a solid:
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([CH3:54])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([CH3:54])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-methylpyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=447, obsd.=447).
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:25][CH2:26][CH2:27][C:28]#[N:29])[N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>C1COCC1>[C:28]([CH2:27][CH2:26][O:25][P:17]([N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)#[N:29]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: O=[N+]([O-])c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(C)C)P(OCCC#N)c1nc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (9.64 g, 84.50 mmol) and triethylamine (14.0 mL, 10.26 g, 101.4 mmol) in THF (200 mL) was added dropwise chloro-2-cyanoethoxy-N,N-diisopropylaminophosphine (20.0 g, 84.50 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale brown oil (24.9 g, 95%). After standing at room temperature, the oil becomes a pale yellow wax-like solid. 1H NMR (CDCl3 δ 8.39 (s, 1H), 4.09 (m, 2H), 3.51 (m, 2H), 2.81 (m, 2H), 1.19 (d, J=6.0 Hz, 6H), 1.07 (d, J=9.0 Hz, 6H). 31P NMR (CDCl3) δ 133.9.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[O:17][N:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[O:17][N:16]=1
Reactant: COC(=O)Cc1cccc(OCc2nc(CCc3nc(-c4ccccc4)oc3C)no2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCc1noc(COc2cccc(CC(=O)O)c2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a mixture of methyl 2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate (0.30 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.28 g, 97%) of 2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([CH3:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH:10]([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Reaction time: 60 h

Procedure:
To a 40 mL vial equipped with a stir bar was added 2,4,6-trichloropyridine (1.00 g, 5.48 mmol), (4-isopropoxyphenyl)boronic acid (1.00 g, 5.56 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (“Pd(dppf)Cl2”, 200 mg, 0.273 mmol), and K3PO4 (3.49 g, 16.4 mmol). The vial was sealed with a septum screwcap and then placed under N2 atmosphere. To the vial was added degassed THF (30 mL). The vial was placed in a 60° C. heating block with stirring for 60 hours. To the mixture was added diatomaceous earth (Celite®). The mixture was filtered and the filtrate was concentrated in vacuo to afford an amber solid residue. This material was subjected to silica gel chromatography (hexanes:CH2Cl2) to afford 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine as a colorless oil that solidified upon standing (710 mg, 46%). 1H-NMR: (400 MHz, CDCl3) δ 7.95-7.90 (m, 2H), 7.58 (d, J=1.5 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 6.99-6.93 (m, 2H), 4.64 (spt, J=6.1 Hz, 1H), 1.38 (d, J=6.0 Hz, 6H); MS: MS m/z 281.9 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[CH3:13].[C:24](=O)([O-])[O-].[K+].[K+].BrCBr>O>[CH3:13][C:7]1[C:6]2[C:11]3=[C:2]([O:1][CH2:24][N:10]3[C:9](=[O:12])[CH:8]=1)[CH:3]=[C:4]([C:14]([OH:23])([C:19]([F:22])([F:20])[F:21])[C:15]([F:16])([F:17])[F:18])[CH:5]=2
Reactant: Cc1cc(=O)[nH]c2c(O)cc(C(O)(C(F)(F)F)C(F)(F)F)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: BrCBr
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)OC2
Reaction time: 4 h

Procedure:
To a solution of 6.8 gm. (0.02 mole) of 8-hydroxy-4-methyl-6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2(1H)-quinolinone is added 2.8 gm. (0.02 mole) of potassium carbonate and 25.3 gm. (0.15 mole) of dibromomethane. The solution is heated and stirred at 70° in a nitrogen atmosphere for 4 hours. At the end of this period the solution is cooled and added to 50 ml. of water. The resultant solid is filtered and purified by chromatography on silicic acid. Elution with 97.5% chloroform/2.5% methanol gives 2.0 gm. of 6-methyl-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, recrystallized from acetonitrile, m.p. 262°-264°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C:24]([OH:28])([CH3:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCO.O>[OH:28][C:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:23]1
Reactant: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1
Temperature: 25 °C

Procedure:
3-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 11.1, 83 mg, 0.18 mmol), pyrimidin-5-ylboronic acid (66.9 mg, 0.540 mmol) and Na2CO3 (57.2 mg, 0.540 mmol) were added to a MW vial and treated with a mixture of DME (764 μL), water (218 μL) and EtOH (109 μL). The vial was sealed, evacuated/purged with argon and the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL) and treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.9 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 20% to 70% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as a yellow solid. UPLC-MS (condition 1) tR=2.47 min, m/z=459.0 [M+H]+, m/z=457.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 3H) 1.68-1.83 (m, 2H) 2.77 (d, J=9.78 Hz, 1H) 2.87 (d, 1H) 2.97-3.07 (m, 1H) 3.21-3.30 (m, 1H) 4.72 (s, 1H) 6.96 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.80-7.89 (m, 3H) 7.94 (dd, J=8.93, 2.32 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H), 9.29 ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1.O1CCCC1.[CH3:21][NH2:22]>>[CH3:21][NH:22][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 60 °C

Procedure:
tert-Butyl 4-(chloromethyl)thiazol-2-ylcarbamate (8.0 g, 24.16 mmol) was dissolved in 2.0 M methylamine in tetrahydrofuran (640 mL, ˜40 eq.) and heated in the microwave for 60 minutes at 60° C. The precipitate (impurity) was filtered off and the filtrate was concentrated under reduced pressure to furnish 1.97 g product as orange foam. 1H NMR (DMSO-d6): δ 11.79 (s, br, 1H), 7.50 (s, 1H), 7.36 (d, 1H), 7.10 (m, 2H), 5.14 (s, br, 1H), 4.63 (s, 2H), 4.36 (s, 2H), 3.83 (t, 2H), 3.43 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][N:16]([CH3:24])[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([C:18](=[CH:17][N:16]([CH3:24])[CH3:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)c(C#N)c1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Starting at room temperature, a solution of 1075 g of 2,4-dichloro-3-cyano-5-fluorobenzoyl chloride (about 94% strength, corresponding to 1010.5 g=4.00 mol) in 850 ml of dichloromethane is added dropwise to a solution of 626 g (4.372 mol) of ethyl 3-dimethylamino-acrylate and 591 g (4.572 mol) of ethyl diisopropyl-amine (Hünig's base) in 1060 ml of dichloromethane. In the course of this, the temperature rises to about 50-55° C. (dropwise addition time about 90 minutes). The reaction mixture is subsequently stirred at 50° C. for 2 hours and then employed in the next stage without further working up.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methanol (532 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (350 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (807 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methoxy)benzoate as an oil. The obtained methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methoxy)benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), 2N sodium hydroxide (2.5 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and crystallized from ethyl acetate/hexane to give the title compound (371 mg, 66%) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH2:35]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>CN(C=O)C.O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH:34]5[CH2:35][N:36]([CH:38]6[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]6)[CH2:37]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(N)C2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CN(C3CCNCC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (100 mg, 0.22 mmol) in DMF (1 mL) was added tert-butyl 4-(3-aminoazetidin-1-yl)piperidine-1-carboxylate (72 mg, 0.25 mmol), HATU (125 mg, 0.33 mmol), and DIEA (80 μL, 0.44 mmol). The reaction mixture was stirred for 1 h. It was then poured into 100 mL of rapidly stirring water. A white solid forms and was filtered, washed with water and dried. This solid was treated with TFA in DCM (3 mL 1:1) for 2 days. The solvent was then removed, and the product purified by reverse phase HPLC, free based and lyophilized to yield a white solid (17.8 mg, 14% yield 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (br. s., 2H) 1.50-1.79 (m, 9H) 1.93 (br. s., 2H) 2.07 (br. s., 1H) 2.35-2.44 (m, 2H) 2.85-3.00 (m, 4H) 3.52 (t, J=7.20 Hz, 2H) 3.94 (s, 3H) 4.05 (t, J=14.02 Hz, 2H) 4.37-4.50 (m, 1H) 4.68-4.84 (m, 1H) 7.47-7.52 (m, 2H) 7.98 (s, 1H) 8.26 (s, 1H) 8.29 (d, 1H) 8.61 (d, J=6.57 Hz, 1H). [M+H] calc'd for C29H38F2N8O3, 585. found 585.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.O>COC(C)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: COCCO
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: COCCOc1cc(C)c([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
To 20 mL of 2-Methoxy-ethanol 243 mg of NaH (6.09 mmol, 60% suspension in oil) were added and the mixture was stirred for 15 min. in an argon atmosphere. 1 g (5.8 mmol) 2-Chloro-4-methyl-5-nitro-pyridine were added and the reaction mixture was stirred for 3 h at room temperature. After addition of 40 mL water and methyl-tertbutyl ether, the phases were separated and the organic phase was washed with saturated NaHCO3 solution and water and was dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using heptane/ethyl acetate=8/2. 2-(2-Methoxy-ethoxy)-4-methyl-5-nitro-pyridine was isolated as colourless oil. Yield: 0.73 g.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[F:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[CH:5][CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CC(C)=O>[N:22]([CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[F:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[CH:5][CH:4]=1)=[N+:23]=[N-:24]
Reactant: O=C(NC1CC1)c1ccc(F)c(-c2ccc(CCl)nn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1ccc(-c2cc(C(=O)NC3CC3)ccc2F)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
3-(6-(azidomethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide. A solution of N-cyclopropyl-4-fluoro-3-(6-methylpyridazin-3-yl)benzamide (430 mg, 1.58 mmol) in 35 mL of DCE was treated with trichloroisocyanuric acid (122 mg, 0.52 mmol) and heated at 90° C. for 1.5 h. Additional trichloroisocyanuric acid (16 mg, 0.07 mmol) was added to the reaction mixture, which was heated for another 30 min at 90° C. The reaction mixture was cooled to RT and the white solid was filtered and rinsed with 2×25 mL of DCM. The filtrate was washed with 5 mL of 0.5 N NaOH followed by 5 mL of brine. The organic layer was concentrated and the residue was purified by silica gel chromatography (35-95% EtOAc in hexanes) to give 3-(6-(chloromethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (228 mg, 47% yield). MS (ESI, pos. ion) m/z: 306.2 (M+1). A solution of 3-(6-(chloromethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (228 mg, 0.75 mmol) in 1 mL of DMF and 1 mL of acetone at RT was treated with NaN3 (68 mg, 1.04 mmol) and the mixture stirred at RT for 5 h. The reaction mixture was filtered through a fritted funnel and the solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated. The brown residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(6-(azidomethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (215 mg, 92% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 313.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1 H, d, J=3.7 Hz), 8.46 (1 H, dd, J=7.3, 2.1 Hz), 8.15 (1 H, dd, J=8.8, 1.8 Hz), 8.07 (1 H, m), 7.90 (1 H, d, J=8.8 Hz), 7.52 (1 H, dd, J=10.5, 8.9 Hz), 4.87 (2 H, s), 2.88 (1 H, m), 0.72 (2 H, m), 0.60 (2 H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −114.48.