Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=C(O)C=C(OCC=C)C=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.[CH3:31][O:32][C:33](=[O:47])[C:34]1[CH:39]=[C:38]([O:40][CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])[CH:37]=[C:36]([OH:46])[CH:35]=1>>[CH3:31][O:32][C:33](=[O:47])[C:34]1[CH:39]=[C:38]([O:40][CH2:41][CH:42]=[C:43]([CH3:44])[CH3:45])[CH:37]=[C:36]([O:46][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[CH:35]=1
Reactant: COC(=O)c1cc(O)cc(OCC=C(C)C)c1
Reactant: Clc1ccccc1CBr
Agent: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(OCC=C(C)C)cc(OCc2ccccc2Cl)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from potassium carbonate (1.25 g, 9.06 mmol), 2-chloro benzyl bromide (0.59 mL, 4.53 mmol), and 3-hydroxy-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester (374a) (1.07 g, 4.53 mmol). Purification by flash column chromatography eluting with 5% EtOAc in hexanes gave a colorless oil (1.60 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.61 (m, 1 H) 7.37-7.45 (m, 1 H) 7.30 (dd, J=3.92, 2.40 Hz, 2 H) 7.27-7.29 (m, 1 H) 7.24 (dd, J=2.27, 1.26 Hz, 1 H) 6.76 (t, J=2.40 Hz, 1 H) 5.49 (tt, J=6.82, 1.39 Hz, 1 H) 5.15-5.23 (m, 3 H) 4.54 (d, J=6.82 Hz, 2 H) 3.92 (s, 3H) 1.81 (s, 3 H) 1.73-1.79 (m, 3 H); LCMS for C20H21ClO4 m/z 383.00 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:33][C:34]#[N:35])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)c1
Yield: 74.5 %

Procedure:
(3,5-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (0.55 g, 1.7 mmol), cyanomethylphosphonic acid diethyl ester (0.52 ml, 3.3 mmol) in anhydrous THF (20 ml), and potassium bis-(trimethylsilyl)amide (0.66 g, 3.3 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile. The crude material was purified by flash column chromatography to give a solid (450 mg, 81%): mp, 135-137° C.; 1H NMR (DMSO-d6) δ 6.67-6.63 (m, 3H), 6.51 (d, J=1 Hz, 2H), 6.36-6.33 (m, 1H), 3.77-3.71 (m, 15H); 13C NMR (DMSO-d6) δ 161.33, 161.16, 160.38, 160.29, 152.70, 152.65, 139.73, 139.63, 138.73, 138.59, 132.82, 132.09, 118.14, 118.05, 107.24, 106.82, 106.62, 106.01, 102.36, 96.32, 95.77, 60.11, 56.06, 55.39; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.44; H, 5.73; N, 3.77.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([Cl:27])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 60 %

Procedure:
A solution of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (448.1 g, 1.24 mole), thionyl chloride (458 g) and toluene (250 ml) was held at reflux for 8 hrs. The excess thionyl chloride and the solvent were stripped off under reduced pressure to give a reddish solid, which upon recrystallization from hexane-toluene afforded 282.9 g of the desired benzoyl chloride as a light yellow crystalline solid; mp 63°-69° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N+:26]([O-])=O)[CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1
Reactant: Cc1c(Cn2c(C(F)F)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c(Cn2c(C(F)F)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (830 mg, 1.788 mmol) and zinc (701 mg, 10.73 mmol) in Acetic Acid (15 mL) was stirred and heated to 60° C. The reaction was monitored by LC/MS. After 90 minutes, a substantial amount of desired product was detected by LC/MS. The reaction was allowed to sit overnight and the next day the mixture was filtered through celite washing with HOAc. The filtrate was concentrated in-vacuo and the resulting residue, while appearing relatively clean and homogeneous by LC/MS, was a mixture of 2 compounds as indicated by TLC. The residue was loaded on a 10 g silica column and eluted with 12% EtOAc/hex for 6 column volumes then a gradient was run from 12% to 35% EtOAc/hex over 15 column volumes successfully separating the two closely eluting compounds. The early eluting compound was the desired product and the fractions were combined and concentrated to give 4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (310 mg, 0.714 mmol, 39.9% yield) as a light yellow solid. LC/MS: MS (ES+) m/e 434.3 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J=7.83 Hz, 1H), 7.12 (t, J=7.83 Hz, 1H), 7.06 (s, 1H), 6.86-7.01 (m, 2H), 6.80 (s, 1H), 6.52 (d, J=7.83 Hz, 1H), 6.23 (d, J=2.02 Hz, 1H), 5.46 (s, 2H), 2.52 (s, 3H)
Reaction SMILES: C1(CC(Cl)=O)CCCCC1.[C:11]([NH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:34])[CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:21]([O:35][C:36](=[O:44])[CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:20]=1)=[O:18])([CH3:14])([CH3:13])[CH3:12]>>[CH:38]1([CH2:37][C:36]([O:35][C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=2[O:25][C:26](=[O:34])[CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:17]([OH:18])[CH2:16][NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)CC2CCCCC2)c(OC(=O)CC2CCCCC2)c1
Agent: O=C(Cl)CC1CCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)CC2CCCCC2)c(OC(=O)CC2CCCCC2)c1

Procedure:
Following the procedure described above in Example 15A but using cyclohexaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(cyclohexaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(cyclohexaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:22]=[CH:21][C:15]2[C:16]([CH2:19][NH2:20])=[CH:17][O:18][C:14]=2[CH:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1.CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:20][CH2:19][C:16]2[C:15]3[CH:21]=[CH:22][C:12]([O:11][C:3]4[S:2][C:10]5[C:5]([N:4]=4)=[N:6][CH:7]=[CH:8][CH:9]=5)=[CH:13][C:14]=3[O:18][CH:17]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
To C-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-yl]-methylamine hydrochloride (100 mg, 0.30 mmol) in DCM (3 mL) was added 4-chlorophenylacetyl chloride (57 mg, 0.30 mmol) and Et3N (0.13 mL, 0.90 mmol). The reaction mixture was stirred (rt, 16 h). Another equivalent of 4-chlorophenylacetyl chloride (57 mg, 0.30 mmol) was added, but the reaction remained at 50% conversion. Two equivalents of 4-chlorophenylacetyl chloride (114 mg, 0.60 mmol) and three equivalents of Et3N (0.13 mL, 0.90 mmol) were added. Upon reaction completion, the mixture was washed with sat'd. aq. NaHCO3 and extracted with DCM. After drying and concentration, the residue was purified by reverse phase HPLC to provide the title compound (47 mg, 35%). MS (ESI): mass calcd. for C23H16ClN3O3S, 449.06; m/z found, 449.9 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.04 (dd, J=7.9, 1.6, 1H), 7.60 (d, J=2.0, 1H), 7.58-7.53 (m, 2H), 7.33-7.29 (m, 2H), 7.28-7.24 (m, 1H), 7.24-7.18 (m, 3H), 5.70 (s, 1H), 4.55 (d, J=5.8, 2H), 3.58 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>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:37][C:34]1[CH:35]=[CH:36][C:31]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][CH:17]=4)[CH:10]=3)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]2)=[N:32][CH:33]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](Nc2ccc(Cl)cn2)C[C@@H]1C
Temperature: 120 °C
Yield: 53 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (80 mg, 0.203 mmol), 2-bromo-5-chloropyridine (78 mg, 0.406 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium tert-butoxide (27.3 mg, 0.284 mmol) were combined in 1,4-dioxane (1 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 15 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3×50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) to give 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (54 mg, 0.107 mmol, 53% yield). LCMS: (Formate, 2 min), Rt=0.86 mins, MH+=506.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O(C(C)(C)C)[Na]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[I:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Ic1ccc(Oc2ccc(I)cc2)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Ic1ccc(Oc2ccc(N3CCOCC3)cc2)cc1
Yield: 94.4 %

Procedure:
The title compound (0.36 g, 99%) was prepared from 4-iodopheyl ether (0.42 g, 1 mmol) and morpholine (0.087 g, 1 mmol) in the presence of Pd2(dba)3 (0.027 g, 0.03 mmol), PtBu3 (0.058 g. 0.28 mmol) and NaO-t-Bu (0.095 g, 1 mmol) in toluene by using the procedure described in step 1 of Example 17: MS (ESI) m/z 382 (M+H); 1H NMR (400 MHz, CDCl3) δ 3.12 (t, J=4.8, 4H), 3.87 (t, J=4.8 Hz, 4H), 6.69-6.72 (m, 2H), 6.89-6.92 (m, 4H), 7.55-7.57 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH2:14])[CH3:8].[C:16]([C@H:19](OS(C)(=O)=O)[CH2:20][CH3:21])(=[O:18])[NH2:17]>C(#N)C>[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH:14][C@@H:19]([C:16](=[O:18])[NH2:17])[CH2:20][CH3:21])[CH3:8]
Reactant: CC[C@@H](OS(C)(=O)=O)C(N)=O
Reactant: CCOC(=O)CCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCCN[C@H](CC)C(N)=O
Temperature: 60 °C

Procedure:
A mixture of powdered caesium carbonate (9.0 g, 27.4 mmol, 5 equiv.), ethyl-4-aminobutyrate (IVb) (1.85 g, 11.0 mmol, 2 equiv.) and methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) (1.0 g, 5.5 mmol, 1 equiv.) in acetonitrile (20 ml, 20 vol.) is heated to 60° C. for 16 hours. The mixture is then filtered and the cake rinsed with acetonitrile (50 ml). Combined filtrates are concentrated to dryness under reducd pressure. The crude methyl-(R)-4-(1-carbamoylpropylamino)butyrate is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22](=O)[CH2:21][C:20]([CH3:26])([CH3:25])[O:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:21][C:20]([CH3:26])([CH3:25])[O:19][C:18]([CH3:27])([CH3:17])[CH2:23]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Yield: 86.8 %

Procedure:
The general McMurry procedure, described for 14 was employed using (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (2.10 g, 7.58 mmol), and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (1.40 g, 8.96 g). Standard work-up followed by purification gave 2.64 g (87%) of the title compound 211 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.37 (s, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 2.16 (s, 2H), 2.10 (s, 2H), 1.13 (s, 6H), 1.12 (s, 6H). LCMS (ESI): m/z 399 and 401 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:8]2[S:9][C:10](C(O)=O)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:38](C)[CH:39]=[O:40].C[Si](N=[N+]=[N-])(C)C>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:8]2[S:9][C:10]([N:38]=[C:39]=[O:40])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=Nc1cnc(N(Cc2ccc(F)cc2)Cc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 2-((4-fluorobenzyl)(4-(pyridin-3-yl)benzyl)amino)thiazole-5-carboxylic acid (850 mg, 2.026 mmol) in dichloromethane (10.100 ml) and the solution was cooled to 0° C. Oxalyl chloride (0.266 ml, 3.04 mmol) and dimethylformamide (0.016 ml, 0.203 mmol) were added and some bubbling occurred. The solution was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0° C., and trimethylsilyl azide (0.538 ml, 4.05 mmol) was added. The mixture was warmed to room temperature, stirred for 30 minutes and concentrated under vacuum. Toluene (5 ml) was added and the mixture was heated to 95° C. for 2.5 hours. The toluene was removed and the resulting solid was triturated/sonicated with ether and filtered with ether washes to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][C:15]#[N:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C[C:21]([S:24]([CH2:27]C#N)(=[O:26])=[O:25])=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14](=[C:27]([S:11]([CH3:8])(=[O:13])=[O:12])[S:24]([CH3:21])(=[O:26])=[O:25])[C:15]#[N:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)CC#N)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)C(C#N)=C(S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(4-tert-butylbenzenesulfonyl) acetonitrile is utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][N:30]=1>O1CCCC1.C(OCC)(=O)C.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH:33]([C:32]2[CH:31]=[N:30][C:29]([Cl:28])=[CH:36][CH:35]=2)[OH:34])(=[O:15])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Reactant: O=Cc1ccc(Cl)nc1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CC(O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In tetrahydrofuran (8 ml), 1-tert-butoxycarbonyl-4-methanesulfonylpiperazine (838 mg) was dissolved, followed by the addition of tert-butyl lithium (a 1.7M pentane solution, 1.72 ml) at −78° C. in an argon gas atmosphere. The resulting mixture was stirred for 2 hours. After the dropwise addition of a solution of 6-chloronicotinaldehyde (346 mg) in tetrahydrofuran (tetrahydrofuran: 4 ml) and stirring at −78° C. for 3 hours, the reaction mixture was added with isopropanol (1 ml). The resulting mixture was heated to room temperature and diluted with ethyl acetate. The diluted solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate, whereby the title compound (532 mg, 54%) was obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N-:22]=[N+:23]=[N-:24].[Na+].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].O>C(#N)C>[N:22]([CH:7]1[C:8](=[O:11])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[Si](OC1=CCC2(CC1)OCCO2)(C(C)C)C(C)C
Agent: [Ce]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=NC1CC2(CCC1=O)OCCO2
Temperature: -20 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of (1,4-dioxaspiro[4.5]dec-7-en-8-yloxy) [tri(propan-2-yl)]silane (22.9 g) in acetonitrile (180 mL) were added dropwise sodium azide (21.4 g) and ammonium hexanitratocerate (IV) (121 g) at −20° C. The reaction mixture was stirred at −20° C. for 4 hr, ice-cooled water was added, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (11.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]2([C:20]3[C:15](=[N:16][CH:17]=[C:18]([OH:21])[CH:19]=3)[O:14][C:13]3[C:8]2=[CH:9][C:10]([C:22]2[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][CH:12]=3)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.CC1OCCC1>[F:28][C:23]1[C:22]([C:10]2[CH:9]=[C:8]3[C@:4]4([N:3]=[C:2]([NH2:1])[CH2:7][O:6][CH2:5]4)[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:19]=4)[O:14][C:13]3=[CH:12][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1ncc(O)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Yield: 15.9 %

Procedure:
A solution of (S)-5′-amino-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-3-ol (0.133 g, 0.352 mmol), potassium carbonate (0.194 g, 1.406 mmol), and neopentyl iodide (0.093 mL, 0.703 mmol) in 1.5 mL DMF was heated to 115° C. overnight. The reaction mixture was then diluted with 2-MeTHF and washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1 EtOAc/MeOH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.025 g, 0.056 mmol, 15.86% yield). MS m/z=449.20 [M+H]+. Calculated for C25H25FN4O3: 448.49.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16]CC)=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].[OH-].[Li+].Cl>O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 131.5 %

Procedure:
Ethyl (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylate (61 g, 0.239 mol, 1.0 eq.) and tetrahydrofuran (700 mL) were charged into a 2 L round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (30 g, 0.714 mol, 3.0 eq.) was dissolved in water (800 mL) and added slowly to the mixture. The reaction mixture was heated at 50° C. for 18 hours. Monitoring the reaction conversion by LCMS showed some residual starting material so lithium hydroxide (20 g, 0.476 mol, 2 eq.) was added. The reaction was stirred further for 5 hours and then stirred at room temperature for 2 days. Monitoring the reaction conversion by LCMS showed complete conversion. The reaction mixture was acidified to pH 3 by slow addition of 1M hydrochloric acid then extracted with ethyl acetate (4×900 mL). The organic extracts were pooled, washed with brine (600 mL), dried over sodium sulfate, filtered and concentrated to dryness. Cyclohexane (100 mL) was added to the dried crude material and concentrated to afford 71.44 g (54.0 g, 100%, corrected for residual solvent) of (1R,2R)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylic acid as a pale yellow solid which contained residual cyclohexane (24.5% w/was calculated from 1H NMR). The compound was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ ppm 5.79 (dt, J=17.01, 9.65 Hz, 1 H), 5.27 (br. s, 1 H), 5.30 (d, J=17.09 Hz, 1 H), 5.14 (d, J=10.38 Hz, 1 H), 2.20 (q, J=8.85 Hz, 1 H), 1.70-1.90 (m, 1 H), 1.52-1.63 (m, 1 H), 1.45 (s, 9 H). LC-MS: purity 100% (UV), tR 1.60 min, m/z [M+Na]+ 250.00.