Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[C:3]([C:8]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N#Cc1ncccc1F
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
30 g of 3-Fluoropyridine-2-carboxamide (C), 120 mL of THF and 768.5 mL of TEA were taken in a reaction flask and cooled to 0-5° C. To this mixture, 72.2 mL of Trifluoroacetic anhydride (in 30 mL of THF) was added dropwise over a period of 30 minutes keeping the reaction temperature below 5° C. (0° C. to 5° C.) and the RM was stirred for 2 hours 30 minutes at a temperature below 10° C. (5° C. to 10° C.). After completion of the reaction, 150 mL of 20% Na2CO3 solution was added dropwise to the RM while maintaining the temperature below 10° C. (5° C. to 5° C.), followed by addition of 360 mL of purified water. The RM was brought to room temperature (RT) and extracted with dichloromethane (MDC) and the organic layer was washed with 300 mL purified water, 150 mL of 2% dil HCl, followed by purified water and brine. The organic layer was dried over Na2SO4 and distilled under vacuum, resulting in the titled compound as a dark brown viscous oily mass. Crude Yield: 22-24 g.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:29][CH:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH:30]([S:32]([NH:35][C:24]([C:23]1[CH:22]=[CH:21][C:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])=[CH:28][CH:27]=1)=[O:26])(=[O:34])=[O:33])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg) was added to a stirred mixture of 4-(t-butoxycarbonyl)benzoic acid (195 mg), 2-propanesulfonamide (98 mg) and 4-dimethylaminopyridine (126 mg) in dichloromethane (3.7 ml). The mixture was stirred overnight, diluted with ethyl acetate, washed (1N HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography, eluting with acetone:hexanes (75:25), to afford the product (193 mg): TLC, Rf =0.64, acetone:hexanes (75:25): MS, m/e=356(M+29), 330(M+3), 329(M+2), 328(M+1), 272, 223, 222, 205, 204, 166.
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[OH:24]>>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[N:10]=[C:9]([NH:8][C@@H:2]1[CH2:1][C@@H:6]3[CH2:7][C@H:3]1[CH2:4][C@H:5]3[OH:24])[CH:18]=[N:17]2
Reactant: CCCCCC(C)Nc1cnc2cc(OC)c(OC)cc2n1
Reactant: CO
Product: COc1cc2ncc(N[C@@H]3C[C@@H]4C[C@H]3C[C@H]4O)nc2cc1OC
Temperature: 22 °C
Reaction time: 24 h

Procedure:
The fungi is stored at −25° C. 250 mL conical flasks each containing 50 mL seed culture medium (medium 216) are inoculated with 2 mL of fungi suspension and incubated on a rotary shaker (200 rpm at 23° C. for 3 days. 250 mL conical flasks each containing 50 mL of the same medium were inoculated with mL of the seed culture and incubated on a rotary shaker (200 rpm ) at 23° C. After 24 hours, (1R,2R,4)- (+)-Bicyclo[2.2.]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine of Example 25 is dissolved in MeOH added to the flasks to a final concentration of 300 mg/L. The cultures are harvested after 24 hours of incubation. (Medium 216: Glucose 0.4%, Yeast extract 0.05%, Soya flour 0.05%, NaCI 0.05%, KH2PO4 0.05.) The extraction is performed using 2 volumes of acetonitrile, 1 volume de tert-butylmethyl ether and volume of n-heptane were added to 1 volume of broth. After magnetic stirring at 22° C, the extract separates to 3 layers. The intermediate layer is collected and evaporated to dryness, and redissolved in ethyl acetate. The ethyl acetate extract is separated on silica gel (0.04-0.063 mm) using ethyl acetate as eluent. Fractions containing the biotransformation product are separated on C1 8 silica using a H2O/MeOH gradient as eluent. This chromatography yields the pure titled compound as an amorphous yellow powder, m.p. 190-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]=[C:8]=[S:9].Cl.Cl.C[CH:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:19][N:18]([CH2:31][CH:32](NC(=O)C2C=CC(C)=CC=2)[CH:33]([CH3:35])[CH3:34])[CH2:17]1.C([NH:53][C@H](C(O)=O)C(C)C)(OC(C)(C)C)=O>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][N:21]1[CH2:20][CH2:19][N:18]([CH2:31][CH:32]([C:5]2([CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH2:4]2)[CH2:6][NH:7][C:8]([NH2:53])=[S:9])[CH:33]([CH3:35])[CH3:34])[CH2:17][CH2:16]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(C(=O)NC(CN2CCN(Cc3ccc(Cl)c(Cl)c3)C(C)C2)C(C)C)cc1
Reactant: COc1cccc(CN=C=S)c1
Agent: Cl
Solvent: ClCCl
Product: COC1=CC=CC(CNC(N)=S)(C(CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)C1
Reaction time: 2 h

Procedure:
3-Methoxybenzyl isothiocyanate (22 mg, 0.12 mmol) was added to a solution of 1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (40 mg, 0.12 mmol) [prepared as described in Example 1 by substituting L-N-BOC-valine with DL-N-BOC-valine] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h and then concentrated. Purification by flash chromatography with 20:1 methylene chloride: methanol as the eluant gave 1-{1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-methoxybenzyl-2-thiourea (18 mg) as a solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=O)[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20]([CH2:23][O:24][NH2:25])([OH:22])=[O:21].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[N:25][O:24][CH2:23][C:20]([OH:22])=[O:21])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: NOCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CON=C1CCCc2cc(OCCn3ccnc3)ccc21
Yield: 43.6 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10 mL of pyridine was treated with 1.02 g (9.3 mmol) of carboxymethoxyamine×0.5 HCl and the solution heated at reflux for 2 days. The solution was diluted with H2O and extracted with EtOAc. On standing, the aqueous phase deposited a solid which was collected and dried. There was obtained 0.56 g (43% yield) of the product as a white solid, mp 193-195° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 330 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([Cl:19])(=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1>>[Cl:19][C:9]1[CH:10]=[CH:11][C:7]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:8]=2)[N:6]=1.[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:9](=[O:18])[CH:10]=[CH:11]2
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Product: Clc1ccc2cc(Br)ccc2n1
Product: O=c1ccc2cc(Br)ccc2[nH]1

Procedure:
The title compound is prepared from 4-bromoaniline and cinnamoyl chloride according to the procedure described in J. Chem. Soc., Perkin Trans. I, 1972, 1648. The crude 6-bromo-1H-quinolin-2-one intermediate obtained is triturated in Et2O/hexanes and filtered to give a beige solid which is used directly in the chlorination step. The crude product is recrystallized in MeOH to afford the title compound as a beige solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:48][C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)=[CH:51][CH:50]=2)=CC=1)([O-])=O>>[N:55]1([C:52]2[CH:51]=[CH:50][C:49]([NH:48][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]6[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]6)=[C:21]([F:24])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:7])=[CH:54][CH:53]=2)[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)OC(C)(C)C)CC4)c3cc2F)CC1
Agent: Cl
Product: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)Nc5ccc(N6CCOCC6)cc5)CC4)c3cc2F)CC1

Procedure:
The title compound was prepared from 4-{6-Fluoro-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester, prepared in the previous step, and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 66a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.74 (d, 1H), 7.44 (d, 1H), 7.27 (m, 2H), 6.88 (m, 2H), 6.32 (s, 1H), 4.27 (m, 4H), 3.86 (m, 4H), 3.54 (tt, 1H), 3.18-3.08 (m, 6H), 2.58 (t, 2H), 2.64-2.35 (br, 8H), 2.30 (s, 3H), 2.12 (m, 4H), 1.96 (m, 2H). LC/MS (ESI): calcd mass 591.3, found 592.4 (MH)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[CH2:34][CH2:35][OH:36])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[CH2:34][CH:35]=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)C(CCO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To a solution of oxalyl chloride (0.62 g, 5 mmol) in CH2Cl2 (20 mL) at −50° C. was added DMSO (0.85 g, 11 mmol, in solution of 5 mL of CH2Cl2) over 2 minutes. 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxyethyl)piperazine (1.85 g, 4.5 mmol, in solution of 5 mL of CH2Cl2) was added. The resulting mixture was stirred at −50° C. for 15 minutes, then triethylamine (2.3 g, 22 mmol) was added. After 5 minutes at −50° C., the mixture was gradually warmed to ambient temperature. At that time the mixture was diluted with CH2Cl2 and washed with water, then brine. The organic layer was then dried over MgSO4 and concentrated in vacuo to afford 1.7 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((formyl)methyl)piperazine as a yellow oil; NMR (CDCl3) 9.8 (d, 1) 7.3 (m, 4), 7.0 (m, 4), 4.6 (m, 3), 3.8-3.2 (m, 7), 2.7-2.2 (m, 4) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(NCc2cccnc2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromoaniline (Aldrich; 1.3 equiv.) in methanol (0.4 M) was treated with 3-pyridinecarboxaldehyde (Aldrich; 1.0 equiv.). The solution was heated to reflux for 2 hours. The reaction was cooled to 0° C. and treated slowly with sodium borohydride (3.4 equiv.). After 1 hour the cooling bath was removed and stirring continued overnight. The reaction was concentrated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was back-extracted once with DCM. The combined organics were washed with water and brine. The organic layer was concentrated to a white solid, which was purified via column chromatography eluting with 90:10 DCM/ethyl acetate to give N-(3-bromophenyl)pyridin-3-ylmethylamine. Anal Calcd for C12H11BrN2: C, 54.77; H, 4.21; N, 10.64. Found: C, 54.67; H, 4.19; N, 10.57. MS found 262.99, 264.99 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)CO>[Ni](Cl)Cl.O>[Br-:1].[C:22]1([P+:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Oc1cccc(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Ni]Cl
Solvent: O
Solvent: OCCO
Product: Oc1cccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 160 °C

Procedure:
Into a separable flask (the capacity: 200 ml) equipped with a condenser and a stirrer, 10.4 g (0.060 moles) of 3-bromophenol, 17.3 g (0.066 moles) of triphenylphosphine, 0.65 g (5 mmole) of nickel chloride and 40 ml of ethylene glycol were placed, and the reaction was allowed to proceed by heating at 160° C. under stirring. After the reaction solution was cooled, 40 ml of pure water was slowly added dropwise. The separated crystals were washed with toluene, separated by filtration and dried, and triphenyl(3-hydroxyphenyl)phosphonium bromide was obtained
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C1C=CC=CC=1.[C-:21]#[N:22].[K+].O1CCOCC1>O>[C:21]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)#[N:22]
Reactant: [O-][n+]1cccc2ccccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: N#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.7 %

Procedure:
To a solution of quinoline N-oxide (2g, 13.8 mmol) was added benzoyl chloride (2.6 mL, 22.0 mmol), followed by water (20 mL). Then, a solution of potassium cyanide (3.6 g, 55.1 mmol) in water (80 mL) was added slowly over a period of 15 minutes with vigorous stirring. Dioxane (15 mL) was added to help the solubility. After the mixture was stirred at RT for 2.5 hours, it was extracted with equal volume of dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was then purified by flash chromatography with 30% of ethyl acetate in hexane. 2.1 g of product was obtained (yield: 100%).
Reaction SMILES: Cl.[OH:2][C:3]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][CH:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:13][N:14]([CH3:25])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:47]([Cl:51])(=[O:50])[CH2:48][CH3:49].CCCl>C(Cl)Cl>[OH2:2].[ClH:32].[C:34]1([C:3]2([O:2][C:47](=[O:50])[CH2:48][CH3:49])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][CH:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13][N:14]([CH3:25])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:5][CH2:4]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[C:34]1([C:3]2([O:2][C:47](=[O:50])[CH2:48][CH3:49])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][CH:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13][N:14]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH3:25])[CH2:5][CH2:4]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[ClH:51]
Reactant: CCC(=O)Cl
Reactant: CN(CC(OCCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1
Agent: CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OC1(c2ccccc2)CCN(CCOC(CN(C)C(=O)OCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Product: O
Reaction time: 0.25 h

Procedure:
670 mg of the compound obtained in EXAMPLE 9 are dissolved in 10 ml of methylene chloride, and 0.2 ml of triethylamine and 0.2 ml of propionyl chloride are then added, with stirring. After 15 minutes, the reaction mixture is washed with water and then with 10% Na2CO3 solution and the organic phase is dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica gel H using DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent. The product obtained is taken up with DCM, acidified to pH 1 by the addition of hydrochloric ether and concentrated under vacuum to give 0.52 g of the expected hydrochloride after crystallization from pentane. M.p.=115° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:35])[C@@H:14]([NH:24][C:25](OCC1C=CC=CC=1)=[O:26])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([O:44][C:45]([NH:47][C@H:48](C(O)=O)[CH2:49][C:50](=[O:52])[NH2:51])=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:35])[C@@H:14]([NH:24][C:25](=[O:26])[C@H:48]([CH2:49][C:50](=[O:52])[NH2:51])[NH:47][C:45]([O:44][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:46])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)[C@H](O)CN2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)[C@H](O)CN2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Yield: 10.5 %

Procedure:
A solution of 730 mg of N-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-(4-methoxyphenyl)butyl]-L-proline tert.butyl ester in 20 ml of ethanol was hydrogenated over 50 mg of 10% palladium-on-carbon for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give an oil which was coupled with 340 mg of N-(benzyloxycarbonyl)-L-asparagine in a manner analogous to that described in Example 1. The crude product was chromatographed on a column of silica gel using 10% methanol in dichloromethane for the elution. There were obtained 82 mg of N-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-(4-methoxyphenyl)butyl]-L-proline tert.butyl ester as a white solid; MS: m/e 613 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])C1C=CC=CC=1OC.[Li+].[OH-:31].Cl>O.C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:14][CH2:15]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:29])=[O:31]
Reactant: COc1ccccc1C(=O)c1cnn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Yield: 88 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.0g, see Example 44), LiOH (1.2 g) in water/ethanol (15 ml /20 ml) was heated at 50° C. overnight. The solution was neutralized with dilute HCl (2M), and extracted with ethyl acetate (200 ml×2), dried over Na2SO4. The solvent was evaporated under reduced pressure and ethyl acetate and diethyl ether was added. The resulting solid was filtered to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid. (0.8g; yield: 88%.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[I-].[K+].C1(=O)[O:30][CH2:29][CH2:28]O1>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:28][CH2:29][OH:30])=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:12][CH2:13][OH:16])=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc(OCCO)cc1)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Temperature: 145 °C
Reaction time: 6 h

Procedure:
A 500 ml round bottom flask is equipped with a mechanical stirrer, thermometer and condenser. Add 50 grams 1,1,1-tris(4-hydroxyphenyl) ethane, 100 grams DMF, 0.5 g. potassium iodide and 47.4 grams of ethylene carbonate. Heat to 145° C. and hold for 6 hours. Add 200 g. ethyl acetate and wash the organic portion four times with 150 g. saturated brine. Strip the solvent from the mix on a rotary evaporator. The yield of tan solid is 78 grams. Recrystallize this crude product by dissolving in 300 g. boiling ethyl acetate and allowing to cool slowly. Collect 70.3 grams of a tan solid; the mp=78-81° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].Cl[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:18].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]([C:16]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:18]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: O=C(c1ccc(O)cc1O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(O)ccc2c1C(F)(F)F
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 1-(2,4-dihydroxy-phenyl)-2,2,2-trifluoro-ethanone (1.00 g, 4.85 mmol) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (1.08 g, 4.85 mmol, 1.0 eq) in anhydrous N,N-dimethylformamide (10 mL) was added potassium carbonate (1.01 g, 7.28 mmol, 1.5 eq). The reaction mixture was stirred at 90° C. for 16 h. The mixture was cooled to room temperature and then poured into ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×100 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by column chromatography eluted with 5% EtOAc/hexane then 30% EtOAc/hexane solution to afford a yellow solid (610 mg, 33.5%) as product. 1H-NMR (CDCl3): δ 7.76 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.41 (dd, J=8.1, 1.9 Hz, 1H), 7.01 to 6.95 (m, 2H), 5.49 (s, 1H); LC-MS (MH+=375/377).
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[Na+].[Cl-].C(O[CH2:11][C:12]1[C:13](=[O:27])[N:14]([CH3:26])[CH2:15][CH2:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=O.[CH2:28]1COCC1>>[O:27]=[C:13]1[C@@H:12]2[C@@:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)([CH2:28][C:4](=[O:3])[CH2:5][CH2:11]2)[CH2:16][CH2:15][N:14]1[CH3:26]
Reactant: COc1cccc(C2=C(COC=O)C(=O)N(C)CC2)c1
Reactant: CCOCC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Na+]
Product: COc1cccc([C@]23CCN(C)C(=O)[C@H]2CCC(=O)C3)c1
Reaction time: 60 h

Procedure:
Ketal cis-34 (Example 16) (20 mg, 0.06 mmol) was dissolved in 1:1 THF/1 N H2SO4 (2 mL) and stirred for 60 h. Ether (2 mL) and saturated NaCl (1 mL) were added, the aqueous phase washed with ether (1 mL), and the combined organic phases washed with saturated NaCl (2 mL), dried, and evaporated to yield 17 mg (99%) of pure cis-9: NMR δ 7.30 (t,J=9 Hz, 1H), 6.9 (m, 3H), 3.78 (s, 3H), 7.87 (s, 3H), 2.63 (s, 2H); IR 1712, 1634, 1603, 1580 cm-1 ; mass spectrum m/e (rel intensity) 287 (32), 218 (26), 55 (100). Anal. Calcd for C17H21NO3 : C, 71.0; H, 7.4; N, 4.9. Found: C, 71.0; H, 7.4; N, 4.9.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[S:12]>Cl>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: O=C(O)c1ccc(N=C=S)cc1

Procedure:
A sample of p-aminobenzoic acid is dissolved in 3N HCl (20% by weight). To this is added about one equivalent of thiophosgene in a single portion. The reaction mixture is stirred until a white precipitate appears, the crude product is filtered, washed with water, and crystallized from acetone-water to give crude p-isothiocyanatobenzoic acid.