Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19])=[O:28]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 156 mg of 2-fluorobenzoyl chloride in 5 ml of tetrahydrofuran. After purification by silica chromatography (eluent: CH2Cl2/MeOH 98/02), 35 mg of (8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoro-methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH3:28].C(O)(=O)/C=C/C(O)=O>C(#N)C>[CH2:27]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[C:6]([F:17])=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)[CH3:28]
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: CCI
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.70 g, 2.54 mmol), acetonitrile (30 ml), potassium carbonate (0.35 g) and 2-iodoethane (0.40 g. 2.54 mmol). Yield: 0.21 g (27%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether: M.p. 109-110° C. MS m/z (rel. intensity, 70 eV) 303 (M+, 13), 302 (10), 289 (16), 288 (bp), 234 (7).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].COC(C)(C)C>CN(C)C=O>[F:25][C:26]1[CH:33]=[C:32]([O:34][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.3 %

Procedure:
560 mg of 5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole were dissolved in 10 ml dimethylformamide. 1.2 g of cesium carbonate and 395 mg 2-Fluoro-4-hydroxybenzonitrile was added and the mixture was stirred at room temperature for three hours. Then 50 ml of methyl-tert-butylether was added, the mixture washed with brine and dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 153 mg of 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile as amorphous lyophilisate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc(Br)cc(OC)c1NC(=O)CC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2CCc3ccccc3C2)cc(OC)c1NC(=O)CC(C)(C)C

Procedure:
Toluene (6 mL) was degassed with nitrogen for 15 min in a 10 mL of microwave tube, then N-(4-bromo-2,6-dimethoxy phenyl)-3,3-dimethyl butanamide (200 mg, 0.6 mmol) and 1,2,3,4-tetrahydroisoquinoline (96 mg, 0.72 mmol) was added, followed by potassium tert-butoxide (101 mg, 0.9 mmol), bis(dibenzylidene acetone)palladium (17 mg, 0.03 mmol), and 2-dicyclohexyphosphino-2-(N,N-dimethylamino)biphenyl (24 mg, 0.06 mmol). The reaction tube was sealed and reacted in microwave at 100° C. for 2 hours. The reaction mixture was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give pure compound as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 8.36 (brs, 1H, exchangeable with D2O), 7.20 (m, 4H), 6.25 (s, 2H), 4.41 (s, 2H), 3.72 (s, 6H), 3.55 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.0 Hz, 2H), 2.07 (s, 2H), 1.03 (s, 9H). MS: 383 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1.[H-].[Na+].[CH3:25][NH:26][C:27](=O)[O:28]C1C=CC=CC=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:22][C:18]1[CH:17]=[C:16]([O:15][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][F:1])[N:12]([C:27]([NH:26][CH3:25])=[O:28])[CH:11]=[CH:10]3)[CH:21]=[CH:20][N:19]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2cc3cc[nH]c3cc2OCCCF)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OCCCF)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
4-((6-(3-Fluoropropoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 33-5 (49.4 mg, 0.164 mmol) was dissolved in N,N-dimethylformamide (1.6 mL), 50-72% oily sodium hydride (14.9 mg) was added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. again, phenyl methylcarbamate described in Production Example 1-7 (62.0 mg, 0.41 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated under vacuum, and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol=99:1-9:1). The target fraction was concentrated under vacuum to obtain the title compound (34.4 mg, 59%).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[Si:10](Cl)(C)C.[OH2:14]>>[C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SiH3:10][OH:14]
Reactant: C[Si](C)(Cl)Cl
Reactant: O
Agent: O=C1CCCCCN1
Product: O[SiH3]

Procedure:
Thirty grams of a commercially available montmorillonite powder was dispersed in one liter of water by a mixer to prepare a montmorillonite suspension. After 20 g of ε-caprolactam was added to this suspension, 50 cc of dichlorodimethylsilane was further added, thus forming an intercalated compound of montmorillonite, ε-caprolactam and silanol. The formation of the intercalated compound was confirmed through X-ray diffraction, infrared absorption spectrum and differential thermal analysis, or the like. X-ray diffraction and infrared absorption spectra confirmed that this intercalated compound was formed into an intercalated compound composed of montmorillonite and nylon 6 when it was heated at about 200° C. for one hour in air to effect polymerization of ε-caprolactam between the layers.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:16](=[O:24])[C:17]([Cl:23])=[C:18]([Cl:22])[C:19]([OH:21])=O)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][CH3:40].CC1NC2C(C=1)=CC=CC=2>>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:16]2([C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH2:29][C:28]4[CH:41]=[CH:42][CH:43]=[C:26]([Cl:25])[CH:27]=4)[C:31]=3[CH2:39][CH3:40])[O:24][C:19](=[O:21])[C:18]([Cl:22])=[C:17]2[Cl:23])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cc2ccccc2n1Cc1cccc(Cl)c1
Reactant: CCCCn1cc(C(=O)C(Cl)=C(Cl)C(=O)O)c2cc(OC)ccc21
Agent: Cc1cc2ccccc2[nH]1
Product: CCCCn1cc(C2(c3c(CC)n(Cc4cccc(Cl)c4)c4ccccc34)OC(=O)C(Cl)=C2Cl)c2cc(OC)ccc21

Procedure:
Following a procedure similar to that described above in part B of this example by using 4-(1-n-butyl-5-methoxy-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid instead of 4-(1-ethyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-(3-chlorobenzyl)-2-ethylindole is substituted for 2-methyl-indole, there is obtained 5-(1-n-butyl-5-methoxy-3-indolyl)-5-[1-(3-chlorobenzyl)-2-ethyl-3-indolyl]-3,4-dichloro-2(5H)-furanone (Formula V: R=CH3 (CH2)2CH2 ; R1 =Y1 =H; R2 =3-ClC6H4CH2 ; R3 =CH3CH2 ; Y=5-CH3O).
Reaction SMILES: [O:1]=[CH:2][C@H:3]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@@H:4]1[OH:5].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:15]1([CH2:14][O:5][C@H:4]2[C@H:6]([O:7][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:8]([CH2:10][O:11][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:9][C@@H:3]2[CH:2]=[O:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
According to Flowchart C, 2,5-anhydro-D-mannose 24, is protected as the dimethyl acetal 25 which is reacted with sodium hydride in dimethylformamide, followed by benzyl bromide giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose, dimethyl acetal 26. Compound 26 is treated with tetrafluoroboric acid in acetonitrile giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 27 which is reacted with diphenyl triphenylphosphoranylidenemethylphosphonate in toluene at reflux, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-4,5,7-tris-O-(phenylmethyl)-D-manno-hept-1-enitol 28. Compound 28 is hydrogenated over palladium on carbon in methanol and acetic acid, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-D-manno-heptitol 29, which is reacted with diphenyl chlorophosphate in pyridine, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-D-manno-heptitol, 7-(diphenyl phosphate) 30, which is then hydrogenated with platinum oxide, giving the product 3,6-anhydro-1,2-dideoxy-1-phosphono-D-manno-heptitol, 7-(dihydrogen phosphate) 31. ##STR11##
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]1[CH2:7][CH2:6]1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:12]([Si:9]([CH3:11])([CH3:10])[O:8][CH:4]([CH:5]1[CH2:7][CH2:6]1)[CH2:3][OH:2])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CO)C1CC1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
To a solution of (tert-butyl-dimethyl-silanyloxy)-cyclopropyl-acetic acid methyl ester (1.66 g, 6.79 mmol) in DCM (27 mL) at −78° C. under a nitrogen atmosphere was added DIBAL-H (20.37 mL, 20.37 mmol, 1.0M in toluene) dropwise. The reaction mixture was stirred at −78° C. for 2.5 hours then at 0° C. for 1 hour before being quenched with Rochelle's salt (30 mL, 1M aqueous solution). The mixture was extracted with ethyl acetate (3×30 mL) before the combined organic phases were dried (Na2SO4) and concentrated in vacuo giving 2-(tert-Butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethanol as a pale orange oil (764 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 3.66-3.49 (2H, m), 3.09 (1H, ddd, J=7.96, 6.40, 3.80 Hz), 1.96 (1H, dd, J=7.43, 5.46 Hz), 0.91 (9H, s), 0.91-0.82 (1H, m), 0.57-0.43 (2H, m), 0.34-0.24 (1H, m), 0.23-0.14 (1H, m), 0.11 (3H, s), 0.07 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=1)([O-:3])=[O:2].Cl.[CH3:21][NH:22][CH3:23].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.[OH-].[Na+]>[CH3:21][N:22]([CH3:23])[CH:16]1[CH2:17][CH2:18][C:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:14][CH2:15]1
Reactant: CNC
Reactant: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 14 h
Yield: 65.6 %

Procedure:
A solution of compound 79 (1.0 g, 3.902 mmol) in dry 1,2-dichloroethane (10 mL) was treated with N,N-dimethyl amine hydrochloride (0.31 g, 3.902 mmol), AcOH (0.22 mL, 3.902 mmol), NaBH(OAc)3 (1.24 g, 5.853 mmol) at room temperature and the resulting mixture was stirred for overnight (14 h). The reaction was diluted with 1 N NaOH (30 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 112 (0.73 g, 66%) as a brown solid. mp 234-236° C.; 1H NMR (DMSO-d6) δ 1.43-1.57 (m, 1H), 1.98-2.06 (m, 1H), 2.12-2.23 (m, 7H), 2.39-2.62 (m, 4H), 6.15 (t, 1H, J=1.5 Hz), 7.54 (d, 1H, J=9.0 Hz), 7.62 (s, 1H), 8.00 (dd, 1H, J=2.1, 9.0 Hz), 8.67 (d, 1H, J=2.1 Hz), 11.82 (s, 1H); ESI-MS m/z (%): 286 (MH+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C@@H:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])[CH2:17][CH2:18][OH:19])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:28])[NH:15][C@@H:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])[CH2:17][CH2:18][O:19][CH3:29])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CCO)c1cccc(Cl)c1F
Reactant: CCOC(C)=O
Product: COCC[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (1R,3S,5R)-3-[(R)-1-(3-chloro-2-fluoro-phenyl)-3-hydroxy-propylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc)=0.82; MS (UPLC/MS): 427.4/429.4 [M+H]+, 471.4 [M+HCOO]−; tR (HPLC conditions a): 3.71 min.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].OS(O)(=O)=O.NC(N)=O.[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17]O)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[N+:1]([O-:4])([O:3][CH2:17][CH:16]([CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:2]
Reactant: CCCCC(CC)CO
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCCCC(CC)CO[N+](=O)[O-]
Reaction time: 1 h
Yield: 97 %

Procedure:
A reactor is charged with 13.48 parts of mixed acid containing 3.33 parts HNO3, 7.77 parts H2SO4 and 2.38 parts H2O. The mixed acid is agitated and its temperature adjusted to 25°±3° C. Urea (0.40 part) is added to the mixed acid over a period of 1/2 hour and the temperature allowed to rise to 32.5°±2.5° C. 2-Ethylhexyl alcohol (5.85 parts) are added to the reactor at a rate of 0.065 part per minute while maintaining the temperature at 32.5°±2.5° C. After addition of 2-ethylhexyl alcohol, the reaction mixture is held at 32.5°±2.5° C. for 1 hour at which time agitation is stopped and the bottom acid layer which forms is drained from the reactor. An aqueous 10% sodium sulfate solution (2.73 parts) is added to the reactor and the resulting mixture agitated. After 15 minutes, agitation is stopped and the bottom aqueous solution layer, which forms, is separated. An aqueous 10% sodium sulfate solution is added to the ethylhexyl nitrate layer which is agitated for 15 minutes at which point 0.50 part of an aqueous 10% sodium carbonate solution is slowly added. An additional 2.73 parts of a 10% aqueous sodium sulfate solution is added to the reactor and agitated for 15 minutes, after which the lower aqueous layer is drained. Another 2.73 parts of 10% aqueous sodium sulfate solution is added to the reactor and the contents agitated for 15 minutes after which 0.50 part 10% aqueous sodium carbonate is added, the agitation stopped and the lower aqueous layer drained. The 2-ethylhexyl nitrate product is obtained in 97% yield, i.e., 7.64 parts.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[CH3:24].[Cl-].[NH+]1C=CC=CC=1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[CH3:24]
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(C)cc3c1C2=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c3c([nH]c2cc1Cl)C(C)(C)c1cc(O)ccc1C3=O

Procedure:
3-Chloro-8-methoxy-2,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S1-2, 18.9 mg, 0.0556 mmol) and pyridinium chloride (220 mg, 34 eq.) were stirred at 185° C. for 2.5 hr. After cooling, the reaction solution was added with water and ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[N:8][C:9]([OH:12])=[N:10][CH:11]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:11]=[N:10][C:9]([O:12][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1)c1ccccc1
Yield: 65.3 %

Procedure:
A solution of 5-(3,4-dichloro-phenoxy)-pyrimidin-2-ol (0.51 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.51 g, 65% yield) as an off-white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>COCCOC>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:13]([CH:19]1[CH2:20][C:21](=[O:22])[NH:17][C:18]1=[O:23])=[O:15])[CH:10]([CH3:11])[CH3:12])=[O:2])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC(=O)NC1=O
Temperature: 5 °C
Reaction time: 6 h

Procedure:
To a cooled (icebath) stirred solution of BOC—L-valine (4.56 g, 0.021 mol), and N-hydroxysuccinimide (2.41 g, 0.021 mol) in DME (50 mL) was added DCC (4.75 g, 0.023 mol). The reaction was stirred for 6 h at 5° C. and then left to stand in the refrigerator over night. The reaction was then cold filtered, washing with Et2O, and conc to yield a solid which was crystallized from EtOAc/hexane to give the desired product as a white crystalline sold (4.59 g, 69.5%): mp 123-124° C.; 1H NMR (300 MHz, CDCl3) δ 5.00-4.95 (d, 1H, J=9.3 Hz), 4.62 (dd, 1H, J=4.97 Hz), 2.85 (s, 4H), 2.75-2.44 (m, 1H), 1.45 (s, 9H), 1.25-0.90 (m, 6H); 13C NMR (CDCl3) δ 168.6, 167.9, 155.1, 155.0, 80.4, 77.4, 77.2, 77.0, 76.6, 76.5, 57.0, 31.6, 31.1, 28.2, 28.1, 28.0, 27.99, 27.93, 25.5, 18.6, 17.3; MS (Cl/CH4) m/z 315 (MH+), 299, 287, 259, 241, 215 (base peak), 173, 172, 145, 144, 116, 100, 72. Anal. Calcd. for C14H22N2O6: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.67; H, 7.06; N, 8.81.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([Cl:14])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:14])[N:5]=[C:6]([CH3:13])[C:7]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1c(Cl)cc(Cl)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Cl)c1CO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
THF (52.3 mL) was cooled to 0° C. in a dry round bottomed flask under an atmosphere of N2. Ethyl 4,6-dichloro-2-methylnicotinate (4.60 mL, 26.1 mmol) was then added followed by diisobutylaluminum hydride (57.5 mL, 57.5 mmol). The reaction was stirred at 0° C. for 3 h. The reaction was then poured into cold saturated sodium potassium tartrate solution. The mixture was stirred for several hours to allow the precipitate to dissolve, then the aqueous phase was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/hexanes) to give (4,6-dichloro-2-methylpyridin-3-yl)methanol. MS ESI calc'd. for C7H7Cl2NO [M+1]+ 192. found 192.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C@@H:11]([CH3:43])[C:12]([NH:14][C@H:15]1[CH2:21][O:20][C:19]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH3:41])[C:16]1=[O:42])=[O:13])C(=O)OC(C)(C)C>CCOCC.CO>[ClH:1].[CH3:2][NH:3][C@@H:11]([CH3:43])[C:12]([NH:14][C@H:15]1[CH2:21][O:20][C:19]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH3:41])[C:16]1=[O:42])=[O:13]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c1cccc2C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@H]1COc2c(cccc2C(F)(F)F)N(Cc2c(C)ccc3ccccc23)C1=O
Yield: 82 %

Procedure:
2 M solution of HCl in Et2O (1.26 mL) was added to a solution of tert-butyl methyl((S)-1-((S)-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (66 mg, 113 μmol) in MeOH (400 μL) After 2.5 h the mixture was concentrated, MeCN was added to the residue and the mixture concentrated. The residue was lyophilized from MeCN/H2O to afford the title compound (48 mg, 82%) as a white powder. MS m/z 486 (MH)+