Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH2:23][CH2:24][CH:25]=[CH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[C:7]([CH3:9])([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[CH2:14]2)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CC(N)C2
Reactant: C=CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCCNC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.220 g; 0.72 mmol), dissolved in DCE (4 mL), is added pent-4-enal (0.060 mg; 0.72 mmol) followed by sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture stirred for 18 h at RT. The reaction mixture was diluted with CH2Cl2, washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to afford 2-methyl-2-(2-pent-4-enylaminoindan-5-ylsulfanyl)propionic acid tert-butyl ester as a crude oil.
Reaction SMILES: [N:1]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH:31]1[CH:30]=[CH:29][C:28]([P:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:33][CH:32]=1.[CH3:8][CH:6]([O:5][C:3](/[N:2]=[N:1]/[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[O:4])[CH3:7]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl azodicarboxylate (DIAD, 1 eq) is added dropwise to a well-stirred solution of triphenylphosphine (1 eq) in THF (0.4 M) at 0° C. under nitrogen. After completion of the addition, the mixture is stirred at 0° C. for an additional 30 min. The white solid obtained is collected by filtration (use medium sized fitted filters) and washed with cold anhydrous THF until the washes are colorless. Finally, the white precipitate is washed once with anhydrous Et2O. The adduct is then dried well in vacuo, and stored under nitrogen. (It is important to store this reagent under anhydrous conditions!) The adduct can be used in place of the separately added reagents in Mitsunobu-type reactions.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[NH:26][N:25]=[CH:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C[C:30]1[CH:35]=[CH:34][C:33](S(OCCC#CCC)(=O)=O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>>[CH2:34]([N:26]1[C:27](=[O:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[CH:24]=[N:25]1)[CH2:35][C:30]#[C:31][CH2:32][CH3:33]
Reactant: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COCOc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC#CCCn1ncn(-c2ccc(N3CCN(c4ccc(OCOC)cc4)CC3)cc2)c1=O
Yield: 60 %

Procedure:
This compound was synthesized as a yellowish amorphous solid from 13 (56.0 mg, 0.147 mmol), 3o (48.2 mg, 0.191 mmol), K2CO3 (40.6 mg, 0.294 mmol), and 18-Crown-6 (38.9 mg, 0.147 mmol) in 60% yield by following general procedure 1.3: 1H NMR (400 MHz, CDCl3, δH) 7.61 (s, 1H), 7.45-7.34 (m, 2H), 7.10-6.87 (m, 6H), 5.12 (s, 2H), 3.97 (t, J=7.3 Hz, 2H), 3.47 (s, 3H), 3.35 (dd, J=6.3, 3.6 Hz, 4H), 3.23 (dd, J=6.3, 3.6 Hz, 4H), 2.63 (tt, J=7.3, 2.3 Hz, 2H), 2.14 (qt, J=7.5, 2.3 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, δC) 152.25, 151.76, 150.85, 146.67, 134.50, 125.93, 123.81, 118.52, 117.50, 116.85, 95.28, 83.95, 75.42, 56.10, 50.72, 49.39, 45.03, 19.25, 14.34, 12.62. MALDI-MS: 462.2 (M+H+), 484.2 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[C:12]([C:17](O)=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:17](=[O:18])[C:12]2[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: NCc1cncc(Br)c1
Reactant: O=C(O)c1ncccc1Cl
Product: O=C(NCc1cncc(Br)c1)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 75, coupling of (5-bromopyridin-3-yl)methanamine with 3-chloro-pyridine-2-carboxylic acid gave the title compound as off-white solid. MS: 326.2 and 328.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[C:10]([NH:14][NH2:15])(=[O:13])[CH2:11][CH3:12]>C(O)C>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:1](=[N:15][NH:14][C:10](=[O:13])[CH2:11][CH3:12])[CH3:2]
Reactant: CC(=O)c1cnccn1
Reactant: CCC(=O)NN
Solvent: CCO
Product: CCC(=O)NN=C(C)c1cnccn1
Yield: 64.2 %

Procedure:
A mixture of 6.11 gm (0.05 mole) of 2-acetylpyrazine, 4.41 gm (0.05 mole) of propanoic acid hydrazide and 100 ml of absolute ethanol is refluxed 10 hr. The mixture is cooled. The white crystals which deposit are collected and dried to yield 6.17 gm (64%) of the title compound having a melting point of 181.3° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[Li+].[OH-].Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)CCc1nc(I)c2c(Cl)nccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1nc(I)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 74A (1.96 g) in tetrahydrofuran (5 mL) and ethanol (1 mL) was treated with 2N LiOH (5.16 ml), stirred at room temperature for 3 hours and then neutralized to pH 3-4 with 3N HCl. The mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4) and concentrated to dryness to give the title compound. MS (ESI(+)) m/e 352 (M+H)+.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:9][NH:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[CH2:30][CH3:31])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[CH2:1]([NH:6][C:7](=[O:8])[N:10]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[CH2:30][CH3:31])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)CC
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
136 μL (1.0 mmol) of pentyl isocyanate are added to 213 mg (0.7 mmol) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]butyrate. The reaction mixture is heated at 100° C. in an Emrys Optimizer microwave oven for 20 minutes. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 291 mg (100%) of ethyl 2-[1-[3′-(3-pentyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate are obtained in the form of a yellowish oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)[C:8]([O:10]C)=[O:9])[CH3:3].[OH-].[Li+].Cl>C1COCC1>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=1)[C:8]([OH:10])=[O:9])[CH3:1]
Reactant: COC(=O)c1ccc(Oc2ccc(SC)cc2)c(CN(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ccc(Oc2ccc(C(=O)O)cc2CN(C)C)cc1

Procedure:
The ester from example 152 (5.22 g, 15.8 mmol) was dissolved in THF (60 mL), treated with aqueous lithium hydroxide (1 M, 63.1 mmol) and heated at reflux overnight. The reaction was neutralised with hydrochloric acid (2 M) and extracted with DCM. The organic extracts were dried (MgSO4) and evaporated to a white foam of the title carboxylic acid (4.80 g, 95%); δH (CD3OD, 400 MHz) 2.48 (3 H, s), 2.56 (6 H, s), 3.94 (2 H, s), 6.80 (1 H, d), 7.00 (2 H, d), 7.33 (2 H, d), 7.94 (1 H, d), 8.09 (1 H, s); MS m/z (ES+) 318 (MH+).
Reaction SMILES: [O:1](P(CC(OCC)=O)(OC1C=CC=CC=1)=O)[C:2]1C=CC=C[CH:3]=1.N12CCCN=C1CCCCC2.[Na+].[I-].[NH2:36][C:37]1[C:42]([CH:43]=O)=[C:41]([CH:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:40]=[C:39]([C:58]2[C:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][CH:67]=3)=[CH:62][CH:61]=[CH:60][C:59]=2[O:74][CH2:75][CH:76]2[CH2:78][CH2:77]2)[N:38]=1>C1COCC1>[CH:76]1([CH2:75][O:74][C:59]2[CH:60]=[CH:61][CH:62]=[C:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][CH:67]=3)[C:58]=2[C:39]2[CH:40]=[C:41]([CH:45]3[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH2:46]3)[C:42]3[CH:43]=[CH:3][C:2](=[O:1])[NH:36][C:37]=3[N:38]=2)[CH2:78][CH2:77]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C=O)c(N)n2)cc1
Reactant: CCOC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3ccc(=O)[nH]c3n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
To a solution of ethyl (diphenoxyphosphoryl)acetate (1.090 g, 3.403 mmol) in THF (15 mL) were added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.520 g, 3.403 mmol) and NaI (0.510 g, 3.403 mmol) followed by a solution of tert-butyl 3-(2-amino-6-(2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-formyl-4-pyridinyl)-1-piperidinecarboxylate (1.000 g, 1.701 mmol), obtained in the step (1) of Example 25-2, in THF (5 mL). The mixture was stirred at 0° C. for 1.5 hrs and quenched with saturated aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3:2 to 1:2) to give tert-butyl 3-(2-{2-(cyclo-propylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate as an amorphous solid (0.276 g, 27%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:18][CH2:17][C@H:16]([S:19]([CH2:21][C:22]3C=CC(Cl)=CC=3)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].C(=O)([O-])O.[Na+].C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1CC#N.C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[C:21]([S:19][C@H:16]1[CH2:17][CH2:18][C@H:13](/[CH:12]=[CH:11]/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:15]1)(=[O:42])[CH3:22]
Reactant: O=S(Cc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N#CCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)S[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
In 11 ml of a mixed solvent of tetrahydrofuran-acetonitrile (8:3) were dissolved 178 mg (0.39 mmol) of 4-chlorobenzyl trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfoxide, and 168 mg (1.57 mmol) of 2,6-lutidine were added to the solution. To the mixture were added 165 mg (0.79 mmol) of trifluoroacetic anhydride with stirring at 0° C. After 3 minutes, an aqueous sodium hydrogencarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The oily residue obtained by evaporation of the solvent was dissolved in 10 ml of methylene chloride, and 119 mg (1.17 mmol) of triethylamine were added to the mixture at 0° C., followed by addition of 62 mg (0.79 mmol) of acetyl chloride to the resulting mixture. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of methylene chloride-hexane (1:1), followed by purification over Rover column [GrosseB, a mixed solvent of ethyl acetate-hexane (1:19)] to obtain 98 mg (yield: 70%) of the title compound having a melting point of 113 to 115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)[CH:7]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12]([NH:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(N)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(N)cc1-c1nc(NC2CCNCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate. LC-MS m/z 463 (M+H)+, 1.73 min (ret time).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[Cl:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:20][C:19]1[C:14]([Cl:13])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([O-:3])=[O:2]
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A solution of 2-nitrobenzoylchloride (7.2 g) in 100 ml toluene was added dropwise to a stirring solution of 2-chloro-3-amino-pyridine (10.0 g) in 100 ml toluene. After the entire amount was added, the mixture was heated to 80° C. for 120 min. After the reaction mixture was cooled down and the resulting 2-nitro-N-(2-chloro-pyridin-3-yl)-benzamide was isolated by filtration. Yield 10.0 g, mp 158-161° C.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:44])=[O:5])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (35 mg, 0.031 mmol) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 31 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:32])[C:28]=1[CH2:29]CBr.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:28]2[C:27]([Cl:32])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:22])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1cncc(Cl)c1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cncc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A mixture of N-Boc-L-tyrosine methyl ester (11.95 g, 40.57 mmol), 3,5-dichloro-4-bromethyl pyridine (see International Patent Application No. PCT/GB99/00589; 10.74 g, 44.56 mmol) and caesium carbonate (14.52 g, 44.56 mmol) in DMF (100 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with citric acid (10%×2), aqueous NaHCO3 (×2) and brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid (18.0 g, 98%). δH (d6 DMSO) 8.72 (2H, s), 7.25 (1H, d, J 8.2 Hz), 7.19 (2H, d, 18.5 Hz), 6.97 (2H, d, 18.5 Hz), 5.20 (2H, s), 4.13 (1H, m), 3.61 (3H, s), 2.95 (1H, dd, J 13.7, 5.0 Hz), 2.82 (1H, m), 1.32 (9H, s) m/z (ESI, 60V) 477 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([O:54][CH2:55][CH2:56][O:57][CH3:58])[CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([O:54][CH2:55][CH2:56][O:57][CH3:58])[CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Reactant: COCCOc1ccc2c(c1)N(C)C(=C1S[CH2+](SC)N(Cc3ccccc3)C1=O)S2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCOC)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 9.08 (1H, s), 7.46 (2H, d), 7.27–7.35 (5H, m), 7.16 (1H, dd), 6.69 (1H, dd), 6.62 (1H, d), 6.51 (1H, d), 5.14 (2H, s), 4.13 (2H, t), 3.75 (2H, t), 3.71 (2H, s), 3.44 (3H, s), 3.19 (2H, s), 2.94 (2H, q), 2.46 (6H, s), 1.02 (3H, t); MS(ESI): 647(MH+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH3:26])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:28][C:2]([F:1])([F:27])[C@:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@@H:13]2[CH3:26])=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccco2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@H]1CN(S(=O)(=O)c2ccco2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-4-(2-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.74-7.71 (m, 1H), 7.46 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 6.74-6.72 (m, 1H), 4.08-4.01 (m, 1H), 3.64-3.57 (m, 1H), 3.42-3.33 (m, 2H), 3.24-3.15 (m, 1H), 2.93-2.87 (m, 1H), 2.77-2.69 (m, 1H), 1.68 (ms, 3H), 1.08 (d, J=9.0 Hz, 3H). m/z (ESI, +ve ion) 419.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.12 μM; GK-GKRP EC50 (LC MS/MS)=50 μM.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([N:16](C(C)C)[CH:17](C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNC>CN(C=O)C.O>[CH3:14][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CCNC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To a solution of N-boc-3-aminopropanoic acid (0.150 g, 0.793 mmol) in DMF (1.5 ml), N-Ethyldiisopropylamine (0.205 g, 1.58 mmol) and HATU (0.301 g, 0.793 mmol) were added and stirred for 5 min. Dimethylamine hydrochloride (0.065 g, 0.793 mmol) was added at RT and the reaction mixture was stirred for 12 h. Water was added to the reaction mixture and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford tert-butyl 3-(dimethylamino)-3-oxopropylcarbamate. Trifluoroacetic acid (1 ml) was added to the product obtained, stirred for 2 h and concentrated to afford title compound as the trifluoroacetate salt (0.090 g, 40%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([Br:16])[C:8]=2[CH:9]=1)=[O:4]>C(O)CCC>[Br:16][C:10]1[C:8]2[CH:9]=[C:5]([CH2:3][OH:4])[O:6][C:7]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(Br)c2cc(C=O)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1ccc(Br)c2cc(CO)oc12
Reaction time: 1 h
Yield: 86 %

Procedure:
Sodium borohydride (1.12 g) was added portionwise to a stirred solution of 2-formyl-4-bromo-7-methoxybenzofuran (30 g) in 1-butanol (150 ml) at ambient temperature. After stirring for 1 h the reaction was quenched by the addition of 2M hydrochloric acid (100 ml) and stirred overnight. The mixture was separated and the organic phase washed with water (200 ml). The combined aqueous phases were extracted with tert-butyl methyl ether (100 ml). The organic phases were combined and concentrated in vacuo followed by drying in vacuo at 60° C. to afford the title compound as a brown solid (26 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]([C:16]([O:18]C)=[O:17])[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4].[OH-].[Na+].OP(O)(O)=O>CO.O>[F:21][C:2]([F:1])([F:20])[C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]([C:16]([OH:18])=[O:17])[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)C1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(c1ccc2c(n1)CCC(C(=O)O)C2)C(F)(F)F

Procedure:
A solution of methyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylate (0.97 g, 3.2 mmol) in methanol (20 mL) was treated with 1 M aqueous sodium hydroxide (6 mL, 2 equiv), and the mixture was heated to reflux. After 1.5 h the cooled mixture was diluted with water (40 mL), adjusted to pH 6 with H3PO4, and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to a solid (0.76 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 2.99-2.83 (m, 4H), 2.77-2.69 (m, 1H), 2.19-2.11 (m, 1H), 1.91-1.81 (m, 1H), 1.54 (s, 6H); m/z=288.4 (M+H)+.