Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[NH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1>C(OCC)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][CH2:19][NH:18][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])=[CH:22]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Solvent: CCOCC
Product: O=C(NCCc1c[nH]c2ccccc12)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 39.3 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 58 mg (0.36 mmol) of tryptamine. After trituration in diethyl ether, 48 mg (40%) of N-[2-(1H-indol-3-yl)-ethyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a light brown solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:12][C:6]1([CH3:13])[N:5]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CCOC(=O)CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 4.8 %

Procedure:
A flask was charged with ethyl (6-bromo-2,2-dimethyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-1(2H)-yl)acetate (120 mg, 0.346 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (288 mg, 0.978 mmol), K3PO4 (277 mg, 1.3 mmol) and DMF (1 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (8.0 mg, 0.0098 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 50° C. for 18 h and at 80° C. for 18 h, water and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, EtOAc to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/heptane to give the title compound (5.6 mg, 5%) as a brown solid:
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[H-].[Na+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:28]([O:4][C@@H:3]1[C@@H:5]([O:6][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)[C@@H:7]([O:8][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)[C@@H:9]([CH2:11][O:12][CH2:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)[O:10][C@H:2]1[S:1][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S[C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 177.6 %

Procedure:
p-Methylphenyl 1-thio-β-D-galactopyranoside (1.0 g, 3.5 mmol) was dissolved in dry DMF (15 mL) and cooled to −10° C. At this temperature (840 mg, 35 mmol) NaH was added and the mixture allowed to warm up to rt. and stirred for an additional 10 min. Then BnBr (4.1 mL, 35 mmol) was added, and the mixture was stirred for 5 h. At 0° C. 10 mL H2O was added and the mixture extracted with EtOAc (3×50 mL). The organic layer was dried over MgSO4 and evaporated to dryness. Flash chromatography using Hexane/EtOAc (5:1) gave the title compound as a white solid (2.01 g, 89%). [α]D22 −1.2° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3), δ 2.27 (s, 3H), 3.56-3.65 (m, 4H), 3.89 (t, 1H, J=9.4 Hz) 3.97 (s, 1H), 4.42 (ABq, 2H, J=11.6 Hz), 4.59-4.60 (m, 3H), 4.70 (m, 3H), 4.73 (ABq, 2H, J=10.1 Hz), 4.95 (d, 1H, J=11.5 Hz), 6.98 (d, 2H, J=8.6 Hz), 7.25-7.47 (m, 22H); 13C-NMR (400 MHz, CDCl3), δ 21.04, 68.68, 72.63, 73.48, 74.34, 75.54, 77.16, 77.24, 84.13, 87.95, 127.36, 127.49, 127.60, 127.65, 127.71, 127.78, 127.86, 128.09, 128.26, 128.35, 129.49, 132.10; HRMS (M+Cs) calcd for C41H42O5SCs 779.1807, found 779.1782.
Reaction SMILES: O[NH:2][C@H:3]([C:19](N)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C(Cl)(Cl)=[O:23].C>C1COCC1>[NH2:2][C@H:3]([C:19]([OH:20])=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NO
Reactant: O=C(Cl)Cl
Agent: C
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 50 °C
Yield: 49.9 %

Procedure:
HO-Tyr(Bzl)-NH2 (20.0 g, 105.7 mmol) was suspended in 300 mL of anhydrous THF and heated to 50° C. Phosgene (20% in toluene) (73.7 mL, 147.4 mmol) was added the amino acid suspension. The amino acid dissolved over the course of approx. 1 hr, forming a pale yellow solution. The solution was concentrated on the rotovap, transferred to a beaker, and hexane was added to precipitate the product. The off-white solid was isolated by filtration and dissolved in anhydrous THF. The solution was stirred over carbon black and subsequently filtered over a bed of Celite. An excess of hexane was added to the filtrate to precipitate the product. The NCA was isolated by filtration and dried in vacuo. 14.3 g (65% yield) of Tyr(Bzl) NCA was isolated as a off-white, solid. 1H NMR (d6-DMSO) δ 9.07 (1H), 7.49-7.29 (5H), 7.12-7.07 (2H), 6.98-6.94 (2H), 5.06 (2H), 4.74 (1H), 3.05-2.88 (2H) ppm.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([C:16]1([NH2:41])[C:22](=[O:23])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[N:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]1=[O:40])=O)C>>[CH:1]1([CH2:6][C:7]([NH:41][C@H:16]([C:22]([NH:41][CH:16]2[C:22](=[O:23])[N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:18]([C:19]3[CH:20]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:17]2=[O:40])=[O:23])[CH3:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7](=O)[CH2:8][C:9]3([O:13]2)[CH2:12][CH2:11][CH2:10]3)=[C:5]([CH3:17])[C:4]=1[OH:18])[CH3:2].Cl.[CH3:20][O:21][NH2:22].C([O-])(=O)C.[Na+].O>CO>[CH3:20][O:21][N:22]=[C:7]1[C:6]2[C:14](=[CH:15][C:3]([CH2:1][CH3:2])=[C:4]([OH:18])[C:5]=2[CH3:17])[O:13][C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: CON
Reactant: CCc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cc2c(c(C)c1O)C(=NOC)CC1(CCC1)O2
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one (0.8 g), methoxyamine HCl salt (500 mg) and sodium acetate (300 mg) in MeOH (20 mL) was stirred at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried and evaporated. The residue was purified by silica gel column eluting with 10% ethyl acetate in hexane, giving 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime (530 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([O:33][C:34](=[O:51])[CH:35]([NH2:50])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:39][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([O:33][C:34](=[O:51])[CH:35]([NH:50][C:1](=[O:3])[CH3:2])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[CH:41][CH:42]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(CC(N)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Acetic anhydride (1.0 mL, 10.8 mmol) and triethylamine (2.4 g, 24 mmol) were added sequentially to a solution of rac.-2-amino-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester p-toluenesulfonic acid salt (5.0 g, 9 mmol) in dichloromethane (100 ml) at 0° C. After 2 h, the reaction mixture was diluted with dichloromethane (250 mL) and washed with 1N HCl (2×20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and dried (Na2SO4). Filtration and concentration provided the crude product which was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give rac.-2-acetamido-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (3.3 g, 8 mmol) in 91% yield.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23][C:24]([CH3:33])([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:25](Cl)=[O:26]>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:25](=[O:26])[C:24]([CH3:33])([CH3:23])[CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Reactant: CC(=O)OCC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C
Yield: 63 %

Procedure:
To the mixture of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (3.0 g, 10 mmol), TEA (15 mL), and DMAP (1.25 g, 10 mmol) in THF (15 mL) was added 2,2-dimethyl-3-acetyloxypropionyl chloride (3.58 g, 20 mmol) prepared in Step A. After the reaction mixture was refluxed for 48 h (90-110° C.), the solvent was removed, and the residue was diluted with an aqueous NaHCO3 solution was added to the residue. The organic material was extracted with EtOAc, and the extracts were washed by 1N HCl, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (2.80 g, 62.9%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:14]([NH2:21])(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(C)C=CC=CC=1>O>[C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:21][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCC1C1=CCCCC1
Reactant: CCCCCC(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC(=O)NC1=C(C2=CCCCC2)CCCC1

Procedure:
2-(1-Cyclohexenyl)cyclohexanone (17.8 g., 0.1 mole), hexanamide (11.5 g., 0.1 mole), 5.0 g. of a highly acidic resin, Amberlyst 15, and toluene (150 ml) are mixed, stirred and heated at reflux for 16 hours. The water formed in the course of the reaction is azeotroped from the reaction mixture. The hot solution is decanted from the Amberlyst catalyst, the catalyst washed with toluene (200 ml.), and the toluene fractions are combined. Pentane (300 ml.) is added to the toluene solution, the mixture chilled in ice and filtered to remove 3.65 g. of unreacted hexanamide. The orange filtrate is stripped to yield 24 g. of crude product, an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]3)[CH:7]=1.[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36]([C:33]2[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=2)=[O:37])=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](CF)[C@H]2CS1
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.5 %

Procedure:
To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (4.70 g) and 5-methoxypyrazine-2-carboxylic acid (2.65 g), in DCM (60 mL) was added N,N-diisopropylethylamine (8.0 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (9.0 g, portionwise over 10 min). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 50% EtOAc in DCM gradient) to afford the title compound (6.71 g, approx. purity 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (m, 9H), 2.71-2.83 (br. s., 1H), 3.03-3.34 (br. s., 1H), 3.81-4.01 (br. s., 1H), 4.09 (m, 3H), 4.48-4.75 (m, 4H), 7.05-7.20 (m, 1H), 7.36-7.58 (m, 1H), 7.93-8.02 (m, 1H), 8.20 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9]1.[CH3:23][C:24]([C:27]([OH:29])=[O:28])([CH3:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:24]([NH:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9]1)([CH3:26])[CH3:23])([OH:29])=[O:28]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1Br
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1Nc2ccc(C(=O)O)cc2CC1(C)C)C(=O)O
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
A mixture of 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.42 mmol), copper(I) iodide (24 mg, 0.13 mmol), 2-methylalanine (170 mg, 1.7 mmol), and potassium carbonate (174 mg, 1.26 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (128 mg, 80%) as a white solid: LC/MS m/e calcd for C22H26N2O4 (M+H)+: 383.46, observed: 383.0.
Reaction SMILES: [C:1](=[N:35]O)([C:8]1[CH:34]=[CH:33][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:31]O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:31][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH:1]([NH2:35])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:34][CH:33]=2)=[CH:19][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ON=C(c1ccccc1)c1ccc(OCCCCOc2ccc(C(=NO)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(OCCCCOc2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The dioxime from Step 2 (6.3 g) is dissolved in ethyl alcohol saturated with ammonia gas (220 ml) and Raney nickel W-6 (2.3 g) added. The mixture is subjected to 650 psi hydrogen pressure and heated to 90° for twenty-two hours. The catalyst is removed by filtration and the solvent is removed by distillation to yield 4.1 g (69% of theory) of colorless crystals mp 120°-123°.
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=CC(SC)=C([C:17]([F:20])([F:19])[F:18])C=2)O1.[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:38](C)=[C:37]([N+]([O-])=O)[CH:36]=[CH:35][C:34]=2[O:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:29][CH:28]=1)(=O)=O)C>>[CH3:22][S:24][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[C:37]([C:17]([F:20])([F:19])[F:18])[CH:36]=[CH:35][C:34]=2[O:43][CH2:44][C:45]([O:47][C:30]([CH3:33])([CH3:31])[CH3:29])=[O:46])=[C:31]([C:17]([F:18])([F:19])[F:20])[CH:32]=1
Reactant: CCS(=O)(=O)c1ccc(-c2c(OCC(=O)O)ccc([N+](=O)[O-])c2C)cc1
Reactant: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Product: CSc1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of example 1 step (ii) using the products from steps (ii) and (iii). Yield 0.564 g. Carried forward to step (v) without characterisation.
Reaction SMILES: [CH3:1][C@:2]([OH:7])([CH2:5]Cl)[CH2:3][OH:4].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:11]=1[CH3:21].[H-].[Na+].O>O1CCOCC1>[CH3:1][C@:2]([OH:7])([CH2:5][CH2:17][C:14]1[C:15]([CH3:16])=[C:10]([O:9][CH3:8])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]=1[O:18][CH3:19])[CH2:3][OH:4]
Reactant: C[C@@](O)(CO)CCl
Reactant: COc1c(C)c(C)c(OC)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
2.4 g (19.6 mmol) of (2R)-2-methyl-3-chloropropane-1,2-diol and 4.28 g (22 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene were dissolved in 20 ml of dioxane and heated to reflux temperature within 1 hour with 1.27 g (66 mmol) of sodium hydride (80% in mineral oil) and 0.1 ml of polyethylene glycol 400 (as the phase transfer catalyst) and stirred at this temperature for 16 hours. The mixture was then treated with 50 ml of water, filtered and washed with water. The residue was recrystallized from ether/hexane and there were obtained 4.91 g of (2S)-2-methyl-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1,2-butanediol in the form of white crystals with a melting point of 82°-84° C. and [α]D20 =+2.86° (c=1.5% in CHCl3).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4].[CH3:18][OH:19]>>[CH3:18][O:19][C:7]1[S:8][C:9]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: CO
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(C)c1
Product: COc1nc(C(=O)O)c(-c2cccc(C)c2)s1

Procedure:
prepared by reaction of 2-bromo-5-m-tolyl-thiazole-4-carboxylic acid methyl ester with MeOH. LC-MS: tR=0.88 min; [M+H]+=250.3.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([O-])=[O:2].C=O.CO.[H][H]>[Pd].O1CCCC1>[OH:2][N:1]=[CH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Agent: [Pd]
Agent: C=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CC=NO)cc1
Yield: 20.7 %

Procedure:
A mixture of methyl 4-(2-nitrovinyl)benzoate (18.6 g, 90 mmol), paraformaldehyde (3.2 g, 108 mmol) and 10% Pd/C (0.9 g) in the mixture of methanol (220 mL) and tetrahydrofuran (220 mL) was stirred at room temperature over 1 atm of hydrogen for 3 h. Then the mixture was filtered and evaporated, purified by column chromatography (silica gel, petroleum ether/ethyl acetate 15:1 to 8:1) to obtain methyl 4-(2-(hydroxyimino)ethyl)benzoate (3.6 g, yield 21%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.55-3.56 (d, J=6.0 Hz, 0.5H), 3.69-3.71 (d, J=5.2 Hz, 1.5H), 3.84 (s, 3H), 6.84-6.87 (t, J=5.6 Hz, 0.75H), 7.45-7.47 (t, J=6.2 Hz, 0.25H), 7.37-7.41 (m, 2H), 7.90-7.91 (m, 2H), 10.68 (s, 0.25H), 11.14 (s, 0.75H); LC-MS (ESI) m/z: 194 (M+1)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][CH2:10][N:9]([C:23]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])=S)[C:8]=12)=[O:3].[H-].[Na+].CI>O1CCCC1>[O:3]=[C:2]1[N:1]=[C:23]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[N:9]2[C:8]3[N:7]([C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)=[CH:11][CH2:10]2)[N:6]=[CH:5][C:4]1=3
Reactant: CCOC(=O)NC(=S)N1CC=C(c2cccc(C(F)(F)F)c2)n2ncc(C(N)=O)c21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 300 mg of [[3-(amino carbonyl)-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-4(5H)-yl]-thioxomethyl]carbamic acid, ethyl ester (Example 12) in 15.0 ml of dry tetrahydrofuran cooled in an ice bath at 0° C. was added 30 mg of sodium hydride (60% dispersion in mineral oil) in one portion. After the evolution of gas ceased the mixture was stirred for an additional 30 minutes at 0° C., then 1.0 ml of methyl iodide was added and the reaction mixture was allowed to warm to room temperature with stirring for 2 hours. The mixture was quenched with water and diluted in water. The aqueous solution was extracted with chloroform. The chloroform extracts were combined and evaporated in vacuo and the residue was triturated with ether. The solid was collected by filtration to give the desired product as a white solid, m.p. 219°-220° C.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][CH2:7][C@@H:8]([CH3:15])[CH2:9]OS(C)(=O)=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][S:21]([O-:23])=[O:22].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([CH3:15])[CH2:9][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1cc(OC[C@@H](C)COS(C)(=O)=O)cc(C)c1Br
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC[C@@H](C)CS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C

Procedure:
Methanesulfonic acid (R)-3-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl ester (148 mg) and sodium methanesulfinate (215 mg) are stirred in 3 mL of N,N-dimethylformamide at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound. Yield: 118 mg.