Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([O:22][CH3:23])(=[O:21])[CH:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[OH:15].C(Br)C=CC>C1COCC1>[CH3:23][O:22][C:13](=[O:21])[C@@H:14]([OH:15])[C@@H:16]([CH2:8][CH:9]=[CH:10][CH3:11])[C:17]([O:19][CH3:20])=[O:18]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(O)C(=O)OC
Agent: CC=CCBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC=CC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of diisopropylamine (14 mL, 100 mmol) in THF at 0° C. was added n-butyllithium (2.5 M in hexane, 40 mL, 100 mmol) over 10 min. The mixture was stirred at RT for 30 min., and then added via cannula to a −78° C. solution of dimethyl malate F-1 (7.71 g, 47.6 mmol) in THF (130 mL). The mixture was warmed to −20° C. over 2 h, and then cooled to −78° C. Crotyl bromide (8.1 g, 60 mmol) was added, then the mixture was allowed to warm to room temperature and then stirred overnight. The solution was then cooled to −10° C. and quenched with NH4Cl (10%, 100 mL). The THF was removed and the residue extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with HCl (1N, 3×50 mL), saturated aqueous sodium bicarbonate (3×50 mL), and brine, then dried over Na2SO4. The solution was filtered and concentrated to give a residue, which was purified on silica gel (ethyl acetate/hexane 1:4) to afford (2S,3R)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester F-2 (2.5 g, 24%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[N:25][CH:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][CH:27]([N:22]5[CH:26]=[N:25][CH:24]=[N:23]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ncn(C2CCNC2)n1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 95 °C
Yield: 49.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (70.75 mg, 0.25 mmol) and 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride (100 mg) 3 ml of dry pyridine under nitrogen was added 152 mg (1 mmol) of DBU and the solution was heated at 95° C. overnight. The orange solution was then concentrated under reduced pressure and water was added to the residue and the solid was collected and dried to yield 50 mg (50%) of a gray solid, m.p. 219.7°-220.7° C. 1H NMR (TFA) δ: 9.8 (s, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 8.11 (d, J=12.5, 1H), 5.85-5.58 (m, 1H), 4.9-4.2 (m, 5H), 3.00-2.7 (m, 2H), 1.75-1.3 (m, 4H). Anal. calcd. for C19H17F2N5O3 : C, 56.86; H, 4.27; N, 17.45. Found: C, 56.80; H, 4.41; N, 17.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+](CC)CC)[CH3:21]>>[F:15][B-:16]([F:19])([F:18])[F:17].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7](=[NH:9])[O:8][CH2:20][CH3:21]
Reactant: CC[O+](CC)CC
Reactant: CCCOc1ccc(Cl)cc1C(N)=O
Agent: F[B-](F)(F)F
Product: CCCOc1ccc(Cl)cc1C(=N)OCC
Yield: 114.9 %

Procedure:
reaction of 5-chloro-2-propoxybenzamide (16.50 g) with triethyloxonium tetrafluoroborate (0.096 mol) yielded crude ethyl 5-chloro-2-propoxybenzimidate tetrafluoroborate (29.14 g);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](S(N)(=O)=O)[CH:5]=[N:6][C:7]=1Cl.BrC1C=CC(S(Cl)(=O)=O)=NC=1Cl.C[N:26](C)[CH2:27][CH2:28][N:29](C)C>>[NH:26]1[C:2]2[CH:3]=[CH:4][CH:5]=[N:6][C:7]=2[NH:29][CH2:28][CH2:27]1
Reactant: CN(C)CCN(C)C
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: O=S(=O)(Cl)c1ccc(Br)c(Cl)n1
Product: c1cnc2c(c1)NCCN2

Procedure:
The 5-bromo-6-chloro-3-pyridinesulfonamide derivative (lix) (prepared from the commercially available 5-bromo-6-chloropyridine sulfonyl chloride as shown in Scheme 18) is condensed with diamine (lxxix), (lxxx) or N1,N1,N2,N2-tetramethylethane-1,2-diamine to form tetrahydropyridopyrazine derivative (I-e), (I-f) or (I-d), respectively, as shown.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)#[N:2].Cl.[NH2:20][OH:21].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:21][NH:20][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(C(=N)NO)ccc21
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Prepared using General Procedure 1. To a flask containing tert-butyl 5-cyano-1H-indole-1-carboxylate INT-65 (200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (177 mg, 2.54 mmol) and Na2CO3 (154 mg, 1.45 mmol). The mixture was stirred at 75° C. overnight then concentrated, re-dissolved in DCM and washed with NaHCO3. The combined organic layers were dried over Na2SO4 and concentrated to provide 222 mg of crude tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate INT-66 as a white solid which was used directly in the next experiment. LCMS-ESI (m/z) calculated for C14H17N3O3: 275.3; found 276.1 [M+H]+, tR=2.25 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[NH:1][C:20]2=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2-c1ccc(F)cc1
Temperature: 90 °C

Procedure:
A mixture of 60d (0.20 g, 0.826 mmol) and 1,1′-carbonyldiimidazole (0.535 g, 3.3 mmol) in DMF (8 mL) was heated at 90° C. for 2 h. The solvent was removed and the residue was triturated with water (15 mL). The resulting precipitate was collected by filtration and washed several times with water. The crude product 60i was used in the next reaction without further purification. MS m/z (M+H+) 287.1.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1.[CH:26]([C:29]1[N:30]=[C:31]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[O:32][C:33]=1[CH:34]([CH3:37])[CH2:35]O)([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.CCOCC>[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:37][CH:34]([C:33]2[O:32][C:31]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[N:30][C:29]=2[CH:26]([CH3:28])[CH3:27])[CH3:35])[CH:19]=1
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)c1

Procedure:
Azodicarboxylic dipiperidide (0.31 g, 1.23 mmol) is stirred in 5 mL toluene at −30 to −20 deg C. Tri-n-butyl phosphine (0.31 mL, 1.23 mmol) is added dropwise and the mixture is stirred at −30 to −20 deg C. 10–15 min. An intimate mixture of (3-hydroxy-phenyl)-acetic acid methyl ester (0.13 g, 0.77 mmol) and 2-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol (0.20 g, 0.701 mmol) in toluene (5 mL) is added dropwise and the resulting mixture is stirred 18 hr at room temperature. The thick suspension is diluted with 25 mL ether and cooled on ice/water for 30 min. The mixture is filtered, concentrated, and purified via silica gel chromatography eluting with 98:2 hexanes:acetone to afford the title compound as a colorless thick oil, 0.10 g, 31%. MS M++1 462. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:14]1([CH2:13][O:3][C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC2CCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.328 g) in N,N-dimethylformamide (15.0 mL), a solution of 4-hydroxybenzaldehyde (1.00 g) in N,N-dimethylformamide (5.00 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. After adding (bromomethyl)cyclobutane (1.22 g), the mixture was stirred at 70° C. for 24 hours. After cooling the reaction mixture to room temperature, 0.5 mol/L hydrochloric acid was added under cooling with ice and three extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to give the titled compound as a colorless oil (1.19 g).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2sc3ccccc3c2c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2sc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with synthesized dibenzo[b,d]thiophene-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 431.87 g/mol.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[O:8]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19]/[C:18]/2=[N:31]/[C:32]#[N:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:2][N:3]1[C:32]([NH2:33])=[N:31][C:18]2([C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:16]=3)[O:21][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[O:4]1
Reactant: CNO
Reactant: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(Oc4ccccc4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of methylhydroxylamine HCl salt (83.6 mg, 1 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25% in MeOH (Wt. %), 0.2 mL, 0.9 mmol), followed by (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 1 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (30 mL). The mixture was filter, and the solvent was removed to give the residue, which was purified by column chromatography to give 2′-methyl-6-phenoxy-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (200 mg, 52%). 1H-NMR (CDCl3): 2.41-2.66 (m, 1H), 2.65 (m, 1H), 2.75 (m, 1H), 3.32 (m, 3H), 5.35 (m, 1H), 6.95 (m, 2H), 7.06 (m, 1H), 7.20 (m, 2H), 7.42 (m, 3H), 7.48 (m, 3H), 7.51 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([N:28]1[CH:32]=[C:31]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[N:29]1)[CH3:27]
Reactant: COC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)OC)nc3)ccn2)cn1
Temperature: 90 °C
Yield: 28.6 %

Procedure:
A mixture of Example C5 (0.12 g, 0.33 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80 mg, 0.36 mmol) and K2CO3 (0.14 g, 0.99 mmol) in dioxane (4 mL) and H2O (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.034 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-((5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide (40 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 10.20 (br s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.31 (s, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.02 (br s, 1H), 7.98 (s, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 4.14 (q, J=7.3 Hz, 2H), 3.21 (s, 3H), 1.37 (t, J=7.3 Hz, 3H), 1.36 (s, 6H); MS (ESI) m/z: 425.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11]Cl)=[CH:6][CH:5]=1.SC1C=CC(C(OC)=O)=CC=1.[Na].[I:26][C:27]1[CH:28]=[N:29][C:30](=[O:33])[NH:31][CH:32]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][N:31]2[CH:32]=[C:27]([I:26])[CH:28]=[N:29][C:30]2=[O:33])=[CH:6][CH:5]=1)=[O:13]
Reactant: COC(=O)c1ccc(SCCl)cc1
Reactant: O=c1ncc(I)c[nH]1
Agent: COC(=O)c1ccc(S)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCn2cc(I)cnc2=O)cc1
Yield: 92 %

Procedure:
A solution of methyl4-(chloromethylthio)benzoate [The methyl 4-(chloromethylthio)benzoate reagent was made in the conventional manner as previously described for its analogues in Preparations 1 and 4 by chloromethylation of methyl 4-mercaptobenzoate; yield 92%](8.2 mmol) in DMF (10 ml) was added dropwise to a stirred suspension of the sodium salt of 5-iodopyrimidin-2-one (8.2 mmol) in DMF (50 ml) and the final mixture heated at 60° C. for 3h. The solvent was then distilled off, the residue triturated with water and with a little ether. The product was a mixture of the N- and O-isomers in the ratio 4:1; yield 1.50 g (45%). The title compound, the N-isomer, was obtained after fractional crystallisation from ethyl acetate and methanol, m.p. 210° C. NMR
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.Cl[O:13][N:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)CC)C>CCOCC>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([C:15]2[CH2:1][C:2]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[O:3]3)[O:13][N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C=C1OC(=O)c2ccccc21
Reactant: FC(F)(F)c1cccc(C=NOCl)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of 109.5 g (0.75 mole) of 3-methylenephthalide and 285 g (1.27 mole) of m-trifluoromethylbenzaldehyde chlorooxime in 3.5 liters of ether was added 128.3 g (1.27 mole) of triethylamine in 250 ml. of ether at 0° C. during 3 hours. The solution was then stirred at room temperature overnight. An infrared spectrum indicated that the reaction was complete. The solid was filtered off. The ethereal solution was washed once with 10% HCl, twice with sodium chloride saturated water, dried over CaSO4 and concentrated under vacuum. Only 19.5 g of impure product was obtained. The solid material which was filtrated from the original reaction solution was stirred with 4 liters of tetrahydrofuran for 4 hours and filtered through a Buchner funnel. The tetrahydrofuran solution obtained was washed once with 10% HCl solution and twice with water saturated with sodium chloride. After being dried and concentrated, the tetrahydrofuran solution gave 140.6 g of pure product, m.p. 170° C.
Reaction SMILES: CO[C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][NH:5]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[C:3](=[O:17])[C@@H:4]3[CH2:8][C@H:7]([O:9][C:10]4[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=4)[CH2:6][N:5]3[C:33]2=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1[C@@H]2C[C@H](Oc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
The compound of formula (II), wherein R11 is 4-bromo, m is 0, W=O, and the bonds depicted as wavy bonds define the 7aS,6S stereoisomer, was prepared as follows. To a solution of cis-4-(4-bromo-phenoxy)-L-proline methyl ester (0.2 g) (0.66 mmol) (Preparation 4) and K2CO3 (0.09 g) (1 eq.) in 10 mL of DMF at 0° C. was added 3,5-dichlorophenyl isocyanate (0.12 g) (1 eq.). The reaction mixture was allowed to warm to 20° C. and was stirred overnight. After adding water, the mixture was extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and evaporated under reduced pressure to afford after SiO2 chromatography (eluent: DCM), the above-titled compound (60 mg). Mp=116° C. NMR (DMSO, 200 MHz): 7.75 (1H, m), 7.5-7.4 (4H, d+d), 6.85 (2H, d), 5.1 (1H, m), 4.6 (1H, dd), 3.95 (1H, dd), 3.35 (1H, dd), 2.7-2.5 (1H, m), 2.25 (1H, bd).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cccnc1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1

Procedure:
A mixture of 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1, 60 mg), pyridin-3-ylboronic acid (25 mg), 2 M Na2CO3 (0.2 mL, 0.4 mmol) and DME (4 mL) was flushed with argon, PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added and the mixture was subjected to MW irradiation at 140° C. for 30 min. The RM was filtered through aa PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 6) tR=0.91 min, m/z=432.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:24]([CH3:26])[CH3:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
N-Tertiarybutyloxycarbonyl-L-tyrosine (14.1 g 50 mM) in dry dimethylformamide (200 ml) was treated with sodium hydride (3.45 g, 115 mM) with vigorous stirring under an atmosphere of argon at 10° C. for 1 h. 2-Bromopropane (6.15 g, 50 mM) was added and the stirred solution allowed to warm to 20° C. over 16 h. Water (200 ml) was added and the solution extracted with ethyl acetate (2×200 ml). The reaction was adjusted to pH1 with hydrochloric acid (6M) and extracted with dichloromethane 2×300 ml. The combined extracts were columned on silica in ethyl acetate to afford N-tertiarybutyloxycarbonyl-O-isopropyl-L-tyrosine (13.6 g, 42 mM) as a foam. The foam was dissolved in dichloromethane (200 ml) and treated with methylamine hydrochloride (2.5 g, 80 mM), 1-hydroxybenzotriazole (6.75 g, 44 mM), dicyclohexylcarbodiimide (9.1 g, 44 mM) and N-methyl morpholine (2.5 g, 80 mM) at 0° C. with continuous stirring. The solution was allowed to warm to room temperature over 16 h and filtered. The filtrate was washed with water, aqueous saturated sodium hydrogen carbonate solution and aqueous citric acid (1M), dried over sodium sulphate and concentrated in vacuo to afford N-tertiarybutyloxycarbonyl-O-isopropyl-L-tyrosine-N-methyl amide (6.1 g, 18 mM) which crystallised from ethyl acetate/hexane as needles m.p. 110°-114° C. (Found: C,63.5; H,8.4; N,8.7. C18H28N2O4 0.25 H2O requires: C,63.4; H,8.4; N,8.2%) δ(CDCl3) 1.32 (6H,d,J=7 Hz, (CH3)2CH); 1.4 (9H,s,(CH3)3C); 2.72 (3H,d,J=4 Hz NHCH3); 2.98, (2H,d,J=7 Hz CH2C6H5); 4.26 (1H,m,NHCHCO); 4.5 (1H, heptet, J=5 Hz, CH(CH3)2); 5.08 (1H,m,NH); 5.92 (1H,m,NH); 6.78, and 7.04 (each 2H,each d,each J=8 Hz C6H4).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH3:20].CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cc(O)ccc1Br
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1cc(OC2CCCCC2)ccc1Br

Procedure:
The title compound was prepared by substituting cyclohexanol for (3-(dimethylamino)phenyl)methanol and 4-bromo-3-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH:9](=[N:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCOC1=O
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCC1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3.84 g of α-amino-γ-butyrolactone hydrogenbromide in 40 ml of dichloromethane is added 2.15 ml of benzaldehyde, followed by5.9 ml of triethylamine and excess magnesium sulfate. After stirring at room temperature for 20 hours, the mixture is filtered and the filtrate concentrated. A 200 ml portion of ether is added and the resulting suspension filtered. The filtrate is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 100 ml portions of ether. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.) to give 3.5 g of N-benzylidene-α-amino-γ-butyrolactone as an oil which solidifies on storage in a freezer: