Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].CSC.C(S)(S)C>>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([C:41]([OH:43])=[O:42])([F:45])[F:44]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Yield: 100 %

Procedure:
Condensation of BocDTrpOPFP (4.70 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 2.98 g.) by the activated ester method using ethyldiisopropylamine gave BocDTrp-Leu-MetNH2 in 71% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MetNH2 using trifluoroacetic acid, methyl sulfide, and ethanedithiol gave HDTrp-Leu-MetNH2 trifluoroacetate salt in 100% yield. Condensation of BocD,LBpaOH (2.95 g.) and HDTrp-Leu-MetNH2 trifluoroacetate salt (3.79 g.) by the mixed anhydride method using diphenylphosphinyl chloride and separation of the diastereoisomers by column chromatography on silica gel using chloroform-methanol (91:9) as eluant gave BocLBpa-DTrp-Leu-MetNH2 and BocDBpa-DTrp-Leu-MetNH2 each in 19% yield. De-t-butoxycarbonylation of BocLBpa-DTrp-Leu-MetNH2 (0.875 g.) and BocLBpa-DTrp-Leu-MetNH2 (0.875 g.) using trifluroracetic acid in methyl ethyl sulfide and ethanedithiol gave HLBpa-DTrp-Leu-MetNH2 and HDBpa-DTrp-Leu-MetNH2, both as the trifluoroacetate salts and both in 100% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][Sn](C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH3:18])[CH:9]=2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2ccc(C)cc2sc1=O
Temperature: 122.5 °C
Yield: 68.3 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (150 mg, 0.48 mmol) in DMF was added tetramethyltin (254 mg, 1.43 mmol) and PdCl2(PPh3)2 (17 mg, 0.024 mmol). The resulting mixture was purged with nitrogen gas for 20 seconds and heated in a 120-125° C. oil bath for 1 h. The reaction mixture was diluted with water (15 mL) and the suspended black solid was filtered off. The clear filtrate was acidified to pH 4 using 1 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (1 mL) and the solid collected to provide 4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (82 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.20 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.17 (m, 2H), 4.00 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.[CH3:22][CH:23]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:22]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:21])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)[CH3:23]
Reactant: CC=O
Reactant: CC1(C)OB(c2ccc(C3CCNCC3)cc2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine in THF was added MeCHO (40%, 0.17 mL, 1.48 mmol) and AcOH (45 mg, 0.74 mmol), the mixture was stirred at room temperature for 20 minutes. Then the NaBH(OAc)3 (157 mg, 0.74 mmol) was added and stirred overnight. The reaction solution was poured to NaHCO3, extracted with EA, dried and concentrated to give product as white solid. MS (m/z): 316 (M+H)+.
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)O.C1C=CC=CC=1.[C:17]([OH:28])(=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=O>NC1C=CC=CC=1.[Cu]>[C:20]1(=[O:22])[O:28][C:17](=[O:27])[C:18]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:19]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C(O)c1ccccc1O
Solvent: c1ccccc1
Solvent: Nc1ccccc1
Product: O=C1OC(=O)c2ccccc21

Procedure:
Decarboxylation is not always a predictable reaction. For example, A. S. Sultanov, J. Gen. Chem. (USSR) 16 1835 (1946) as abstracted in CA 41:6223(e) discloses that salicylic acid may be decarboxylated by autoclaving the acid in the presence of copper bronze and benzene at 170° C. The acid alone decarboxylates at 205° C., while in the presence of aniline decarboxylation begins at 170° C. In the case of salicylic acid, aniline and copper bronze seem to be equal in catalytic ability. On the other hand, when phthalic acid is heated in aniline at 180° C., decarboxylation does not occur and instead phthalic anhydride is produced. Heating phthalic anhydride with copper bronze in chloroform at 180° C. gave a 22% yield of benzoic acid. Phthalic acid was found to decarboxylate to yield benzoic acid merely by heating in water at 235° C.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[C:26]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](O)=[O:41])=[CH:36][C:35]=1[OH:45])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40]([O:25][CH2:24][CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][CH:7]=3)=[C:2]([OH:1])[CH:21]=2)=[O:41])=[CH:36][C:35]=1[OH:45])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Product: O=C(COc1ccc(C(=O)c2ccccc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
Following the general procedure of Example 17, the title compound is prepared by reacting equimolar amounts of the alcohol compound of Example 7 and 4-benzoyl-3-hydroxy-phenoxyacetic acid.
Reaction SMILES: C1(=O)NC(=O)CC1.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[NH2:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32]>C(#N)C.O>[OH:33][CH:30]([CH2:31][OH:32])[CH2:29][NH:28][C:8](=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: NCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C1CCC(=O)N1
Solvent: O
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)CO
Yield: 87 %

Procedure:
To a solution of cis-9-octadecenoic acid succinimide (18.3 g, 48.2 mmol) in 50 ml of acetonitrile is added 1-amino-2,3-propanediol (4.4 g, 48.2 mmol) in 50 ml of H2O. After stirring for 12 hours at room temperature the acetonitrile is distilled off and the residue is extracted with ethyl acetate. The combined organic phases are extracted with saturated NaCl solution. The organic phase is dried with MgSO4, filtrated and concentrated. The residue is crystallized from isohexane. Yield: 87% of a colorless powder.
Reaction SMILES: [NH:1]1[C@:9]2([CH2:11][OH:12])[O:10][C@:2]1([C@H:5]([C@@H:7]2[OH:8])[OH:6])[CH2:3][OH:4].[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(OCC)C>CN(C)C=O>[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][N:1]2[C@:9]3([CH2:11][OH:12])[O:10][C@:2]2([C@H:5]([C@@H:7]3[OH:8])[OH:6])[CH2:3][OH:4])=[CH:16][CH:15]=1
Reactant: OC[C@]12N[C@](CO)(O1)[C@@H](O)[C@@H]2O
Reactant: Fc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2CCOc1ccc(F)cc1

Procedure:
A solution of a compound Formula XIV (2.60 g, 0.0159 mol), 2-(4-fluorophenoxy)ethyl bromide (3.70 g, 0.0169 mol), and Na2CO3 (1.86 g, 0.0175 mol) in 11 mL of dimethylformamide was heated at 85° C. for 8 h. The solution was cooled, then treated with 250 mL of ethyl ether portion wise, and the solvent was removed. The resultant residue was diluted with chloroform, filtered, and concentrated. This crude material was chromatographed on a Waters Prep-500 HPLC (88:11:1, CHCl3 /MEOH/NH4OH) to give the product, which was recrystallized from EtOAc/hexane (3.49 g, 73%), mp 96°-98° C. (corrected). 1H NMR supported the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:24][CH3:25])=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].O>CC(N(C)C)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N:26]=[N+:27]=[N-:28])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:24][CH3:25])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1OC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(N=[N+]=[N-])cc2C(F)(F)F)C[C@@H]1OC
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid methyl ester (500 mg, 1.123 mmol, intermediate in the synthesis of example 58) in DMA (5 ml) was added sodium azide (146 mg, 2.246 mmol) and the reaction mixture was heated to 50° C. for 26 h. Then water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were dried (Na2SO4) and evaporated. The remaining brown oil was purified by silica gel chromatography (DCM/EtOAc 95:5) to obtain the title compound (351 mg, 77%) as light brown oil. MS (EI): 466.2 (M+OAc)−.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.C1(N)CC1>CN(C=O)C>[CH:38]1([NH:34][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][S:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)[CH2:40][CH2:39]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and cyclopropanamine (9.16 uL, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer).The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid 1H NMR (CHLOROFORM-d) δ: 8.42 (br. s., 1H), 7.78 (d, J=1.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.13 (br. s., 1H), 6.85 (d, J=9.1 Hz, 2H), 6.17 (d, J=2.3 Hz, 1H), 5.05 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.42 (dd, J=10.4, 3.5 Hz, 1H), 3.53 (br. s., 2H), 3.34 (br. s., 4H), 3.14 (td, J=12.9, 2.3 Hz, 1H), 2.99 (td, J=12.8, 2.7 Hz, 1H), 2.78-2.93 (m, 3H), 2.68 (br. s., 4H), 2.39 (dd, J=13.6, 1.3 Hz, 1H), 0.80-0.90 (m, 2H), 0.54-0.67 (m, 2H). [M+H] calc'd for C23H28N6O2S, 479; found, 479.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([OH:15])[CH:17]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Yield: 89.4 %

Procedure:
To 1.5 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 40 mL of absolute ethanol was added 1.1 g of 3-hydroxy-4-methylaniline. After stirring the reaction under an inert atmosphere for 16 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ether/hexanes. Drying in vacuo yielded 1.9 g (90%) of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile as a yellow powder: melting point 236-239° C. (decomposed); mass spectrum (m/e): M+H 294.9.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]([CH:12]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][NH:20]3)CC)=[N:7]2.NC1C=CC=C(Cl)C=1C(O)=O.NC1C=CC=C(C)C=1C(O)=O.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)[CH2:64][O:65][C:66]([CH3:69])([CH3:68])[CH3:67].O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC>>[C:66]([O:65][CH2:64][CH:12]([C:6]1[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:4](=[O:31])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[N:7]=1)[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][NH:20]2)([CH3:69])([CH3:68])[CH3:67]
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Reactant: CC(C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cc1cccc(N)c1C(=O)O
Agent: Nc1cccc(Cl)c1C(=O)O
Product: CC(C)(C)OCC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1ccccc1

Procedure:
2-[2-tert-butoxy-1-(9H-purin-6-ylamino)-ethyl]-3-phenyl-3H-quinazolin-4-one was prepared using the general procedure described above with respect to compound 14, but 2-amino-6-chlorobenzoic acid was substituted for 2-amino-6-methylbenzoic acid in step A, 2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the conditions used in step C removed both the benzyl protecting group and the A-Ring chloro substituent.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[O:4][C:5]2[C:10]([C:11]=1[CH2:12]Cl)=[CH:9][C:8]([Br:14])=[C:7]([OH:15])[C:6]=2[Br:16].ClC1C=C2C(=CC=1O)[O:25][C:24](=[O:30])[CH:23]=C2CCl>>[C:24]([O:30][CH2:12][C:11]1[C:10]2[C:5](=[C:6]([Br:16])[C:7]([OH:15])=[C:8]([Br:14])[CH:9]=2)[O:4][C:3](=[O:17])[C:2]=1[Br:1])(=[O:25])[CH3:23]
Reactant: O=c1cc(CCl)c2cc(Cl)c(O)cc2o1
Reactant: O=c1oc2c(Br)c(O)c(Br)cc2c(CCl)c1Br
Product: CC(=O)OCc1c(Br)c(=O)oc2c(Br)c(O)c(Br)cc12
Yield: 30 %

Procedure:
This compound was prepared by the same method as compound 4, starting with compound 13 rather than compound 12, to yield 34.5 mg (73.3 mmol, 30% yield) of compound 6 as an oil. 1H NMR (CDCl3+5% CD3OD) δ 7.88 (1H, s), 5.42 (2H, s), 2.11 (3H, s); MS (ES, negative) 466.9, 468.9, 470.9 and 472.9; UV (KMOPS, pH 7.2) λmax (ε) 397 nm (15,900 M−1cm−1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:16]2[CH2:17][NH:18][CH2:19][CH2:20][S:21][C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl.C(N(CC)CC)C>ClCCl>[C:1]([N:18]1[CH2:17][C:16]2[C:11]([Cl:10])=[CH:12][CH:13]=[CH:14][C:15]=2[S:21][CH2:20][CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoyl chloride (3.93 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (2.82 g) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 15 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol/water. Yield 5.93 g (m.p. 64°-72° C.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH3:7])[N:4]([CH3:8])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14](Cl)=[O:15]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([O:10][CH3:9])[C:19]=1[O:20][CH3:21])[C:14]([NH:1][CH:2]1[CH2:6][N:5]([CH3:7])[N:4]([CH3:8])[CH2:3]1)=[O:15]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN1CC(N)CN1C
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)NC2CN(C)N(C)C2)cc(OC)c1OC

Procedure:
To 10 g (0.09 mole) of 4-amino-1,2-dimethylpyrazolidine in chloroform was added with stirring 20.7 g. (0.09 mole) of 3,4,5-trimethoxybenzoyl chloride. After 30 minutes of stirring the solution was extracted with dilute sodium hydroxide. The chloroform solution was dried (sodium sulfate), filtered, and the filtrate concentrated. The resulting crystalline material was recrystallized from equal portions of ethyl acetate and isopropyl ether. The product (12.1 g.; 44%) melted at 163°-166° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cccc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
Intermediate 1-1 (566 mg, 2.0 mmol) and 2,6-dimethoxyphenylboronic acid (437 mg, 2.4 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(2,6-Dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a beige solid (375 mg, 49% yield) after flash column chromatography purification. MS (M+1)=385.4.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:22]([F:23])=[C:21]2[C:8]([CH2:9][C:10]3([C@H:19]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:20]42)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:7][C:6]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O>CO.N1C=CC=CC=1>[F:4][C:5]1[C:22]([F:23])=[C:21]2[C:8]([CH2:9][C:10]3([C@H:19]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:20]42)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:7][C:6]=1/[C:30](=[N:2]/[OH:3])/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NO
Reactant: C[C@@H]1CN2c3c(cc(C(=O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: C[C@@H]1CN2c3c(cc(/C(=N/O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 90 °C

Procedure:
Hydroxylamine hydrochloride (77 mg, 0.001 mmol) was added to a solution of (2R,4S,4aS)-rel-9,10-difluoro-2,4-dimethyl-8-(phenylcarbonyl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 13, 280 mg, 0.6 mmol) in methanol:pyridine (1:1, 3 mL) and the solution was heated to 90° C. for 12 hours. Solvents were removed and the residue was subjected to silica gel column chromatography using a gradient of ethyl acetate in pet. ether to give the title compound as a racemic mixture. Yield: 120 mg (42%).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (20 mL) was added a solution of 4-(trifluoromethyl)phenyl isocyanate (0.41 g, 2.2 mmole) in dry dichloromethane (3 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. The resulting mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and 2N aqueous HCl. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield the title compound as an orange solid (0.36 g, 49% yield), mp=81–83° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−25.6° (c=1, EtOH).
Reaction SMILES: C(O[C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:44][C@@H:45]([OH:48])[CH2:46][CH3:47]>>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([O:48][C@H:45]([CH3:44])[CH2:46][CH3:47])=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH2:31]4)(=[O:25])=[O:24])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: CC[C@@H](C)O
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3O[C@H](C)CC)[nH]c(=O)c2nn1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
The title compound of Example 78 (400 mg, 0.84 mmol) was added to a mixture of potassium bis(trimethylsilyl)amide (840 mg, 4.2 mmol) in (R)-2-butanol (4 ml) and the mixture stirred at 110° C. for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water (10 ml) and neutralised using 2N hydrochloric acid. This aqueous suspension was extracted with ethyl acetate (3×30 ml), the combined organic extracts washed with sodium hydroxide solution (20 ml), brine (2×30 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by is column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100:0 to 97.5:2.5) and the product suspended in ether and evaporated under reduced pressure. This solid was recrystallised from hexane/ethyl acetate to afford the title compound (72 mg, 17%) as a white solid. [α]D=−20.88° (c=0.083, dichloromethane) Found: C, 54.65; H, 6.63; N, 19.25. C23H33N7O4S;0.5H2O requires C, 53.89; H, 6.69; N, 19.13% δ (CDCl3): 1.06 (6H, m), 1.40 (3H, t), 1.50 (3H, d), 1.86 (1H, m), 1.99 (1H, m), 2.42 (2H, q), 2.58 (4H, m), 3.04 (2H, q), 3.16 (4H, m), 4.09 (3H, s), 5.56 (1H, m), 8.62 (1H, s), 9.05 (1H, s), 10.70 (1H, s). LRMS: m/z 504 (M+1)+