Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCC1CCNCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 40.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.636 g, 1.77 mmol) and 4-butylpiperidine (0.226 g, 1.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF38) (0.245 g, 27%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.8, J=8.8 Hz, 1H), 4.54 (q, J=32.4, J=14.8, 2H), 3.94-3.90 (m, 2H), 3.77 (s, 3H), 2.90 (d, J=11.2 Hz, 1H), 2.72 (d, J=10.8 Hz, 1H), 2.25-2.10 (m, 3H), 1.93 (t, J=11.2 Hz, 1H), 1.80 (t, J=11.2 Hz, 1H), 1.61 (d, J=10.8 Hz, 2H), 1.31-1.19 (m, 9H), 0.90-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.3, 155.5, 139.7, 129.8, 117.2, 107.1, 103.3, 68.0, 64.2, 55.9, 55.7, 54.5, 45.5, 36.5, 36.0, 32.9, 32.5, 29.2, 29.2, 23.1, 16.9, 14.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH2:42]O)[CH:35]=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=2)(=[O:54])=[O:53])=[C:47]([CH2:65][C:66]2[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=2[F:73])[CH:46]=1>C1COCC1.C(OCC)C>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH2:42][CH2:41][CH2:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=2)(=[O:53])=[O:54])=[C:47]([CH2:65][C:66]2[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=2[F:73])[CH:46]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: OCCCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCCc2cccnc2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 0.25 h

Procedure:
To 1.5 g of triphenylphosphine dissolved in 25 ml of THF is added 0.909 g of diisopropyl azodicarboxylate. After 15 minutes at room temperature, 0.61 g of 3-pyrid-3-ylpropan-1-ol is introduced and the mixture is left at 20° C. for 15 minutes. 1.36 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide are introduced and the mixture is left at room temperature for 18 hours. The medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a toluene/ethyl acetate mixture passing from a ratio of 9/1 to 5/5 (v/v). 5 ml of 2M hydrochloric acid are added to the product obtained, dissolved in diethyl ether, and the solvents are then evaporated off. The residue is taken up in diisopropyl ether to give, after filtration, 0.55 g of the expected product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:7]=2)[N:13]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.202 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.013 g, 6%). MS (ISP) 447.0 [(M+H)+]; mp 247° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=[C:2]1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[C:7]([NH:26][C:47](=[O:48])[CH2:46][C:43]3[CH:42]=[CH:41][C:40]([O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])=[CH:45][CH:44]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=[C:2]1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc(-c4cccs4)s3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc(-c3cccs3)s2)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Under an argon atmosphere, to a mixture of 3-(2,2′-bithiophen-5-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7m) (350 mg, 752 μmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11m (298 mg, crude) as a brown oily substance. Rf=0.26 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.22 (s, 6H), 0.92 (s, 9H), 0.94 (s, 9H), 3.64 (s, 2H), 6.76-6.85 (AA′BB′, 2H), 6.98-7.05 (AA′BB′, 2H), 7.06-7.13 (m, 2H), 7.19-7.27 (AA′BB′, 2H), 7.33 (d, 1H, J=3.6 Hz), 7.36 (d, 1H, J=3.6 Hz), 7.54-7.59 (m, 1H), 8.05-8.11 (AA′BB′, 2H), 8.91 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C@H:9]([OH:17])[CH2:8][CH2:7]1)=O.[OH-].[Na+]>CO.O>[NH2:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C@H:9]([OH:17])[CH2:8][CH2:7]1
Reactant: O=C(N[C@H]1CC[C@@H](O)c2ccc(F)cc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N[C@H]1CC[C@@H](O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 65 h
Yield: 86 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1S,4R)-7-fluoro-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide (synthesised in an analogous manner to that described in WO 2009/048474, which is incorporated herein by reference in its entirety) (2.31 g, 8.34 mmol) in MeOH (22.5 mL), was added a solution of sodium hydroxide (0.834 g, 20.8 mmol) in water (15 mL) and the mixture was stirred at RT for 65 h. The mixture was concentrated in vacuo, then applied to an SCX-2 cartridge (50 g), washing with methanol then eluting basic components with 0.2-1 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.29 g, 86%). 1H NMR (300 MHz, d6-DMSO): 1.60-2.15 (6H, m), 3.62-3.71 (1H, m), 4.49 (1H, t, J 4.7), 5.15 (1H, br s), 6.98 (1H, dt, J 8.6, 2.8), 7.28 (1H, dd, J 10.7, 2.8), 7.36 (1H, dd, J 8.6, 6.2).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH:6]([NH:10][CH:11]1[CH2:13][CH2:12]1)[C:7](=[O:9])[CH3:8])[CH3:3].[N:15]1([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[C:24](O)=[O:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:14])[CH:6]([N:10]([CH:11]1[CH2:12][CH2:13]1)[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:22]=1)[C:7](=[O:9])[CH3:8])[CH3:3]
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(NC1CC1)C(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(C)=O)N(C(=O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1)C1CC1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To 0.4 g (2 mmol) of 2-cyclopropylamino-3-oxo-butyric acid ethyl ester hydrochloride salt, 0.6 g (2 mmol) of 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid, 0.4 g (2 mmol) of EDCI and 0.3 g (2 mmol) of HOBT was added 2 ml of DMF and 0.6 ml (4 mmol) of triethylamine. The mixture was stirred for 3 h after which time the solvent was removed by evaporation; the residue was then re-dissolved in EtOAc, washed with 10% citric acid solution, saturated sodium hydrogen carbonate solution, dried with sodium sulfate and re-concentrated to afford 0.8 g (93%) of crude 2-[cyclopropyl-(3-morpholin-4-yl-5-trifluoromethyl-benzoyl)-amino]-3-oxo-butyric acid ethyl ester. This material was re-dissolved in 5 ml of EtOH and 1 g (8 mmol) of ammonium trifluoroacetate was added. The solvent was evaporated and the residue heated to 130° C. for 16 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 6:4] afforded 0.4 g (55%) of the title compound as colorless solid. MS: 424.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[NH:10][C:9]2=[O:19])=[CH:4][C:3]=1[O:20][CH:21]([CH3:23])[CH3:22].S(OC)(O[CH3:28])(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]=[C:9]2[O:19][CH3:28])=[CH:4][C:3]=1[O:20][CH:21]([CH3:23])[CH3:22]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)c(OC(C)C)c1

Procedure:
using 3-(4-chloro-3-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with dimethyl sulphate and sodium bicarbonate in acetone there is obtained 1-(4-chloro-3-isopropoxyphenyl)-2-methoxy-4-trifluoromethyl -6(1H)-pyrimidinone. m.p. 55°-58° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.[NH4+].[Cl-]>CCO.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[CH3:11]
Reactant: Cc1ncc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ncc(N)cc1Br
Temperature: 75 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 3-bromo-2-methyl-5-nitropyridine (2.3 g, 10.5 mmol) in EtOH (20 mL) was added water (40 mL), NH4Cl (2.25 g, 42 mmol) and iron powder (2.94 g, 52.5 mmol). The mixture was stirred at 75° C. for 2 hours. After the reaction mixture was cooled to room temperature, it was filtered through a celite pad. Organic solvent was removed under reduced pressure, and it was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4, and solvent was removed to give an off-white solid (1.52 g, 77%).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]>C(O)C>[C:5]([NH:9][CH:8]=[N:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH:11]=1)#[N:1]
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Solvent: CCO
Product: N#CNC=Nc1cccc(-c2csc(NC(=N)N)n2)c1
Yield: 161.2 %

Procedure:
A solution of 9.33 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole and 3.93 gm of ethyl N-cyano-formamidate in 65 ml of ethanol was stirred at room temperature overnight. The crystalline product which separated out was collected by filtration, washed with cold ethanol and dried, yielding 9.2 gm of the title compound, mp. 215° C. (dec.)
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])([O:3]CC)=O.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([N:18]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:15])[C:8]=2[CH2:7][CH2:6][C:1]1=[O:3])[CH3:17]
Reactant: CCOC(=O)CCC1C(=O)CCCC1=O
Reactant: CCN
Product: CCN1C(=O)CCC2=C1CCCC2=O

Procedure:
21.2 g (0.1 mol) of 2-(2-carbethoxy-ethyl)-cyclohexan- 1,3-dione and 200 ml of 24% ethanolic ethylamine solution are heated to 180° C. in a stirred autoclave for 3 hours. The reaction solution is evaporated down using a rotary evaporator and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate (1:1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[C@@H:13]([OH:21])[CH2:12][N:11]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16](=[O:20])[N:17]([CH3:18])[CH3:19])[C:13](=[O:21])[CH2:12][N:11]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
(2S,5R)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(dimethylcarbamoyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 133, 2.194 g, 5.29 mmol) in DCM (65 mL) was cooled in an ice-bath then Dess-Martin periodinane in DCM (26.5 mL, 7.94 mmol) was added and the reaction was stirred at rt overnight. The organic solution was washed with sat. Na2S2O3, sat. NaHCO3, brine, dried over MgSO4, filtered and evaporated. The crude product was purified via flash chromatography (10-75% EA/EtOAc) to obtain the desired product (1.050 g, 48.1%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@H:3]1[O:17][CH3:18].O=[CH:20][CH2:21][CH2:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].C(O)(C(F)(F)F)=O>>[CH:26]1([C:24]([NH:23][CH2:22][CH2:21][CH2:20][NH:1][C@@H:2]2[C:11]([CH3:13])([CH3:12])[C:10]3[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=3[CH2:4][C@H:3]2[O:17][CH3:18])=[O:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Reactant: O=CCCNC(=O)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NCCCNC(=O)C1CCCCC1

Procedure:
Following the process of Example 11(c) using (6R,7R)-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide and cyclohexanecarboxylic acid (3-oxo-propyl)-amide the TFA salt of the title compound was prepared. (m/z): [M+H]+ calcd for C24H37N3O3, 416.28; found, 416.5.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=3)[CH:7]=[CH:8]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Product: FC(F)(F)c1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-(trifluoromethyl)-1H-indole and iodobenzene: ESMS m/e: 262.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.C(OCC)(=O)C.[ClH:33]>O1CCCC1>[ClH:33].[ClH:33].[NH2:8][C@H:12]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)=[CH:16][N:17]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ncc(-c3cccc(Br)n3)s2)COC1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@@H](CO)c1ncc(-c2cccc(Br)n2)s1
Temperature: 90 °C

Procedure:
To a solution of (S)-4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (5.00 g, 11.4 mmol) obtained in Step 2 in tetrahydrofuran (30 ml) was added 4N hydrogen chloride-ethyl acetate solution (30 ml) and heated to reflux at 90° C. for 2 hours. After the reaction solution was cooled, it was concentrated and washed with ethyl ether and dried, and the title compound (3.57 g) was obtained.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:7])[C:4]([O-:6])=[O:5].[C:8]1([CH:14]([NH3+])C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[F:1][CH2:2][CH:3]([OH:7])[C:4]([O:6][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CC([NH3+])c1ccccc1
Reactant: O=C([O-])C(O)CF
Agent: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(O)CF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-phenylethanaminium 3-fluoro-2-hydroxypropanoate (11-1) (0.14 g, 0.61 mmol) in DMF (1 mL) was added benzyl bromide (0.087 mL, 0.73 mmol). The mixture was stirred at room temperature overnight, diluted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to provide 11-2. HRMS: 198.0688 found, 198.0692 required (M+).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.CC(C)N=C=N[CH:16]([CH3:18])[CH3:17]>CN(C=O)C>[CH:17]1[CH:16]=[C:18]2[C:4]([CH:3]=[C:2]([C:1]([OH:8])=[O:7])[O:6][C:4]2=[CH:3][CH:2]=1)=[O:6]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCOC(=O)CCC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(=O)c2ccccc2o1

Procedure:
LP-1 ctrl was synthesized by following Scheme 1 (FIG. 14). Rink SS resin was deprotected and loaded with monoethyl succinate (5 eq) and DIC (5 eq) in DMF for 2 hrs. The rest of the amino acids were added successively and the final product was purified by following the same methods described above.
Reaction SMILES: [Na:1].C(C1(CCO[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[CH2:47]([C:49]1([CH2:56][CH3:57])[O:53][CH:52]([CH2:54][OH:55])[CH2:51][O:50]1)[CH3:48]>>[Na:1].[CH2:56]([C:49]1([CH2:47][CH3:48])[O:53][CH:52]([CH2:54][O:55][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])[CH2:51][O:50]1)[CH3:57]
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: CCC1(CC)OCC(CO)O1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: CCC1(CC)OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)O1
Yield: 14.3 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using (2,2-diethyl-1,3-dioxolan-4-yl)methanol obtained in the step (65b) above to obtain the title compound (418 mg, total 14.3% yield) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:6]=2[N:7]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33](O)=[O:34])=[N:30][CH:31]=1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:18]=[C:17]([NH:19][C:33](=[O:34])[CH2:32][C:29]4[CH:28]=[CH:27][C:26]([Br:25])=[CH:31][N:30]=4)[CH:16]=[N:15][CH:14]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:6]=2[N:7]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: CC(C)(CO)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 34 at 50° C. using [2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3-yl)methanone (Preparation 48) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a yellow solid in 60% yield, 75 mg. LCMS (System 10): Rt=2.69 min; m/z 524 [M+H]+
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31](Cl)(=[O:33])=[O:32])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH:16]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=1[S:31]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)(=[O:33])=[O:32])([CH3:17])[CH3:18]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1OC

Procedure:
As described under 1.2, 8.25 g (0.04 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 13.3 g (0.044 mol) of 2,4,6-tris(isopropyl)benzenesulfonyl chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/-hexane, 14.25 g (75%) of α-(2,4,6-tris(isopropyl)phenylsulfonyl-oxyimino)-3,4-dimethoxy-benzyl cyanide are obtained in the form of beige crystals having a melting point of 90.5-93.5° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 352 nm (ε=11000) that extends to 433 nm. Elemental analysis: C25H32N2O5S (472.6)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.Cl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: CSc1ccc(NC(=O)CC(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(NC(=O)CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Benzyl 3-(4-(methylthio)phenylamino)-3-oxopropanoate (150 mg, 0.476 mmol) was dissolved in MeOH (1.5 ml). NaOH 1M (500 μl) was added, and the reaction was stirred at 40° C. for 2 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with EtOAc. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum to give 3-(4-(methylthio)phenylamino)-3-oxopropanoic acid (90 mg, 84% yield).
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 62.9 %

Procedure:
A mixture of i-propyl 4-chloro-3-nitrobenzoate (25.88 g, 0.11 mol), 3-bromoaniline (17.36 ml, 0.16 mol) and potassium carbonate (14.63 g, 0.11 mol) in N-methyl-2-pyrrolidone (25 ml) is heated to 150° C. for 3 days. After cooling the mixture is poured into diluted hydrochloric acid (300 ml, 1 M). The precipitate is filtered off, washed with water and dried (37.4 g). This crude product is washed with hot 2-propanol to afford pure 24 (26.25 g, 65%). Mp 162-165° C.