Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[C:31]([F:42])[C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.CO>C1COCC1.[Pd]>[NH2:39][C:32]1[C:31]([F:42])=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 78.1 %

Procedure:
A suspension of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate (810 mg, 1.351 mmol) and Pd/C (10% wt, 144 mg, 0.135 mmol) was stirred under hydrogen (1 atm) in THF (10.0 mL) and MeOH (5.0 mL) overnight. The mixture was filtered through 45 um disc and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate (601 mg, 78% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81-1.11 (m, 3H), 2.14-2.26 (m, 1H), 2.91-3.03 (m, 3H), 3.19 (s, 3H), 3.86 (s, 3H), 5.80 (d, J=4.5 Hz, 1H), 5.88 (br. s., 2H), 7.15-7.25 (m, 2H), 7.40 (dd, J=12.1, 2.5 Hz, 1H), 7.44 (s, 1H), 7.70 (s, 1H), 7.80 (dd, J=2.4, 1.5 Hz, 1H), 7.84-7.94 (m, 2H). LCMS (m/z, ES+)=570.3 (M+H+).
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:10]([NH:12][C@H:13]([C:32](O)=[O:33])[CH2:14][C:15]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])[CH:16]=1)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[C@@H:44]([OH:50])[C@H:45]([CH:47]1[CH2:49][CH2:48]1)[OH:46]>>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:14][C:15]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])[CH:16]=1)[C:32]([NH:42][C@@H:43]([CH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[C@@H:44]([OH:50])[C@H:45]([CH:47]1[CH2:49][CH2:48]1)[OH:46])=[O:33])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 4, by condensing N-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamoyl]-1-(2,4-dinitrophenyl)-L-histidine with (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol there is obtained (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-(2,4-dinitrophenyl)imidazole-4-propionamide as a yellow solid; MS: 797 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1.Cl[CH2:15][C:16](Cl)=[O:17].Cl>[Na]>[C:16]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1)(=[O:17])[CH3:15]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Agent: Cl
Agent: [Na]
Product: CC(=O)NC1CCc2c(C)cc(C)c(O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.77 Grams of 1-amino-4,6-dimethyl-7-hydroxyindane was dissolved in 100 ml of 0.2N-sodium hdyroxide aqueous solution, then 1.7 g of α-chloroacetyl chloride was added thereto under an ice-cooling condition. Then the reaction mixture was stirred at a room temperature for 2 hours. The reaction mixture was acidified by adding a diluted hydrochloric acid, then extracted with chloroform. The chloroform layer was washed with water, dried, then the solvent was removed by evaporation. Recrystallized from ethanol to obtain 2.34 g of 1-acetylamino-4,6-dimethyl-7-hydroxyindane in the form of colorless needle-like crystals. Melting point: 131°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]([C:32]2([C:35](=[O:44])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:34][CH2:33]2)=[O:31])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]2[CH:13]=[C:12]([C:14](O)=[O:15])[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=2[N:8]=[CH:9][N:10]=1.[N:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>C(OCC)(=O)C>[F:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:35]([C:32]2([C:30]([NH:29][C:27]3[CH:26]=[CH:25][C:3]([O:4][C:5]4[C:6]5[CH:13]=[C:12]([C:14](=[O:15])[NH:53][CH2:52][CH2:51][N:45]6[CH2:50][CH2:49][O:48][CH2:47][CH2:46]6)[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:7]=5[N:8]=[CH:9][N:10]=4)=[C:2]([F:1])[CH:28]=3)=[O:31])[CH2:33][CH2:34]2)=[O:44])=[CH:38][CH:39]=1
Reactant: C[Si](C)(C)CCOCn1c(C(=O)O)cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc21
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(C(=O)NCCN2CCOCC2)cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.05 g, 0.08 mmol, 1.0 eq.), 2-Morpholin-4-yl-ethylamine (0.016 ml, 0.12 mmol, 1.5 eq), HATU (0.076 g, 0.2 mmol, 2.5 eq), TEA (0.033 ml, 0.24 mmol, 3.0 eq), and dry DMF (5 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with (2×) H2O (50 ml), sat'd NaHCO3 (2×), 5% LiCl (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo, giving cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-(2-morpholin-4-yl-ethylcarbamoyl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide as a cream solid (0.049 g, 83% yield). MS (ESI) for C36H43F2N7O6Si: 736 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:16][CH:17]1[C:23](=[O:24])[N:22]2[CH:25]([C:29]([NH:31][CH:32]([C:41](=[O:54])[CH2:42][O:43][C:44](=[O:53])[C:45]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[O:30])[CH2:26][CH2:27][CH2:28][N:21]2[C:20](=[O:55])[CH2:19][CH2:18]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][CH:17]1[C:23](=[O:24])[N:22]2[CH:25]([C:29]([NH:31][CH:32]([C:41](=[O:54])[CH2:42][O:43][C:44](=[O:53])[C:45]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[CH2:33][C:34]([OH:36])=[O:35])=[O:30])[CH2:26][CH2:27][CH2:28][N:21]2[C:20](=[O:55])[CH2:19][CH2:18]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
TFA (25 ml) was added dropwise to an ice cold stirred solution of the ester 216e (2.11 g, 3.0 mmol). The mixture was stirred at 0° C. for 20 min then at room temperature for 1 h. The mixture was evaporated to dryness then coevaporated with ether three times. Addition of dry ether (50 ml) and filtration afforded 1.9 g (98%) of 217e as a colourless solid: mp 126-130° C.; [α]D30 −122.0 (c 0.1, MeOH); IR (KBr) 3322, 1740, 1658, 1651, 1532, 1433, 1277, 1150; 1H NMR (D6-DMSO) δ8.87 (1H, d, J=7.4), 8.61 (1H, d, J=7.8), 7.92-7.86 (2H, m), 7.65-7.43 (6H, m), 5.25-5.12 (3H, m), 4.94-4.60 (2H, m), 4.44-4.22 (1H, m), 3.43-3.10 (1H, m), 3.00-2.52 (3H, m), 2.45-2.10 (3H, m), 2.10-1.75 (2H, m), 1.75-1.50 (2H, m); Anal. Calcd for C29H28Cl2N4O9.1H2O: C, 52.34; H, 4.54; N, 8.42; Cl, 10.66. Found: C, 52.02; H, 4.36; N, 8.12; Cl, 10.36. MS (ES−) 649/7/5 (M−1), 411 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][C:3]=1I.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C.[CH2:47]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH3:56])[CH2:48][C:49]#[CH:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CC#N>[CH3:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[O:1][C:49]([CH2:48][CH2:47][N:51]4[CH2:55][CH2:54][CH2:53][C@H:52]4[CH3:56])=[CH:50][C:3]=3[CH:4]=2)[CH:13]=[CH:12][C:11]=1[C:14]#[N:15]
Reactant: C#CCCN1CCC[C@H]1C
Reactant: Cc1cc(-c2ccc(O)c(I)c2)ccc1C#N
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: Cc1cc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)ccc1C#N
Temperature: 55 °C
Yield: 55 %

Procedure:
The product from Example 106C (670 mg, 2.00 mmol), palladium (II) acetate (22 mg, 0.10 mmol), tri-o-tolylphosphine (61 mg, 0.20 mmol), copper (I) iodide (114 mg, 0.60 mmol), and diisopropylamine (2.8 mL, 20 mmol) were dissolved into a 0.1M MeCN solution of (R)-1-but-3-ynyl-2-methylpyrrolidine (30 mL, 3.0 mmol) and heated at 55° C. overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and chromatographed through a short column of silica with a 10 to 100% gradient of EtOAc/CH2Cl2 to provide the impure title compound as an orange-brown foam (55% yield), a portion of which was purified by HPLC [Waters Nova-Pak HR C18 column (40 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL min.]. TFA salt: MS (AP) m/z 345 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.68-1.82 (m, 1 H), 1.99-2.23 (m, 2H), 2.30-2.44 (m, 1 H), 2.60 (s, 3 H), 3.22-3.90 (m, 7 H) 6.82 (s, 1 H), 7.55-7.87 (m, 6 H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:34]([O:41]CC)([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37]>>[C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32][P:34]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CBr)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(C[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)OCC
Yield: 44 %

Procedure:
A solution of compound 4 (0.08 g, 0.16 mmol) in 10 mL of (EtO)3P was stirred at 140° C. for 24 h and the solvent was evaporated under reduced pressure. The residue was dissolved in 10 mL of MeOH and adsorbed on silica gel and then purified on silica gel column chromatography (Hexane:EtOAc=1:2 to 1:4 v/v) to give compound 5 (0.04 g, 0.07 mmol) in 44% yield. 1H NMR (CDCl3, 400 MHz) δ 8.97 (br, 1H), 8.08 (d, J=7.2, 2H), 8.04 (d, J=7.6, 1H), 7.92 (d, J=7.2, 2H), 7.60 (m, 3H), 7.50 (m, 4H), 5.98 (d, J=18.4, 1H), 5.65 (d, J=4.8, 0.5H), 5.52 (d, J=4.8, 0.5H), 5.45 (m, 1H), 4.76 (m, 1H), 4.11 (m, 4H), 2.42 (m, 2H), 1.32 (m, 6H); MS calcd for C27H29FN3O8P m/z 574.2 (M+H)+, found 574.3.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C

Procedure:
To an ice cooled stirring solution of 2-[(2-cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6.53 g) in chloroform (75 ml), was added N-bromosuccinimide (4.02 g). The reaction mixture was allowed to warm to room temperature and after 16 h treated with water and extracted twice with DCM. The combined extracts were washed with dilute sodium metabisulphite then dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as an orange foam, yield 7.96 gm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:11]2[CH2:13][CH2:12]2)[CH:9]=O)[C:3]=1[O:14][CH:15]([F:17])[F:16].N1CCCCC1.C(O)(=O)C.[C:28](OCC)(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:4]([C:3]=1[O:14][CH:15]([F:17])[F:16])=[C:8]([CH:11]1[CH2:13][CH2:12]1)[CH:9]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]2=[O:35]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=CC(c1nccc(Cl)c1OC(F)F)C1CC1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc(C2CC2)c2c(OC(F)F)c(Cl)ccn2c1=O
Temperature: 100 °C

Procedure:
71.6 mg of 2-(4-chloro-3-difluoromethyl-2-pyridyl)-2-cyclopropylethanal (XII) was dissolved in 3 ml of anhydrous ethanol, to which were added 80 μl of piperidine, 80 μl of acetic acid and 220 μl of diethyl malonate and the resulting mixture was heated at 100° C. for 5 hours. The solvent was distilled off by under reduced pressure, and thereafter, the resulting mixture was diluted with ether, and the resulting organic layer was washed with water and saturated salt water, and dried over anhydrous sodium sulfate, and the solvent was distilled off by under reduced pressure. 2 ml of Dowtherm A was added to the resulting residue, and the resulting mixture was heated at 240° C. for 30 minutes. The reaction solution was purified directly by silica gel column chromatography (eluent; hexane→hexane:ethyl acetate=1:1) to obtain 51.3 mg of ethyl 8-chloro-1-cyclopropyl-9-difluoromethyl-4-oxo-4H-quinolidine-3-carboxylate (XIII).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:45]([N:47]([CH2:60][CH3:61])[S:48]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)(=[O:50])=[O:49])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:54]2[CH:53]=[CH:52][C:51]([S:48](=[O:49])(=[O:50])[N:47]([CH2:45][CH3:46])[CH2:60][CH3:61])=[CH:56][CH:55]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: CCN(CC)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)OC)cc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.20 g, 0.50 mmol) in dimethoxyethane (10 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.030 g, 0.11 mmol), palladium (II) acetate (0.013 g, 0.055 mmol), 4-(N,N-diethylsulfamoyl)phenylboronic acid (0.175 g, 0.68 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford [6-chloro-4-(4-diethylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.035 g, 15%) as a solid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH2:5][Cl:6])[CH:3]=[O:4].[CH3:8][C:9]1([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:6][CH2:5][C:2]([Cl:7])([Cl:1])[CH:3]([OH:4])[CH:13]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:12]([C:9]1([CH3:8])[CH2:10][CH2:11]1)=[O:19]
Reactant: CC1(C(=O)Cn2cncn2)CC1
Reactant: O=CC(Cl)(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)C(C(O)C(Cl)(Cl)CCl)n2cncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
11.3 g of 2,2,3-trichloropropionaldehyde were added dropwise to 9.2 g (0.056 mol) of 1-methyl-1-(1,2,4-triazol-1-yl-acetyl)-cyclopropane in 120 ml of tetrahydrofuran and 13.6 g (0.1 mol) of potassium carbonate, the temperature increasing slightly. The reaction solution was stirred overnight at room temperature and was thereafter introduced into 500 ml of water. The resulting precipitate was filtered off under suction and recrystallized from methanol. 5.5 g (30% of theory) of 1,2,2-trichloro-3-hydroxy-4-(1,2,4-triazol-1-yl)-5-(1-methylcycloprop-1-yl)-pentan-5-one of melting point 182° to 186° C. were obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]45[CH2:24][CH:23]4[CH2:22][NH:21][CH2:20]5)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][CH2:26]N(C(C)C)C(C)C.C(I)C>CN(C=O)C>[CH2:25]([N:21]1[CH2:22][CH:23]2[C:19]([C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9]4)=[CH:14][CH:15]=3)([CH2:24]2)[CH2:20]1)[CH3:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(N2CCN(c3ccc(C45CNCC4C5)cc3)CC2)cc1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CC2CC2(c2ccc(N3CCN(c4ccccc4)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of trihydrochloride salt of 1-(4-(4-phenylpiperazin-1-yl)phenyl)-3-azabicyclo[3.1.0]hexane (0.92 g, 2.19 mmol) in dry DMF (6 mL) was added DIPEA (1.21 g, 6.44 mmol)) followed by addition of ethyl iodide (0.197 mL, 2.4 mmol). The reaction was stirred at r.t. for 3 h under argon. After completion of reaction as confirmed by TLC, crude compound was extracted with ethyl acetate (60 mL) and was given water washings (3×30 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed in vacuo to afford the crude compound which was purified by column chromatography (silica gel 0.8:9.2 MeOH:DCM) to afford pure title compound (0.61 g, 74%).
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:15][P:16]([S:22][CH:23]([CH3:25])[CH3:24])([S:18][CH:19]([CH3:21])[CH3:20])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH2:30](OCC)C>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:22][CH:23]([CH3:25])[CH3:24])([S:18][CH:19]([CH3:21])[CH3:20])=[S:17])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(SC(C)C)SC(C)C)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(SC(C)C)SC(C)C
Reaction time: 0.08 h

Procedure:
Ethyl-N-[bis(isopropylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (4.0 g.) was dissolved in 10 ml. of 35% hydrobromic acid in acetic acid for one hour. Diethyl ether was added and a viscous oil precipitated. The ether was decanted and the precipitate washed with diethyl ether an additional three times. The precipitate was dissolved in acetonitrile and excess propylene oxide added. After about 5 minutes, the solution was concentrated in vacuo to yield ethyl-N-[bis(isopropylthio)phosphinothioylmethyl]glycine (0.95 g.) as an oil, ND25 =1.5524. The compound gave the following analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH:23]([O:37]C(=O)C)[CH2:24][CH:25]([C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[NH:10][C:11]([C:13]2[CH:22]=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH:9]([NH:10][C:11]([C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:12])[CH:23]([OH:37])[CH2:24][CH:25]([C:32]1[NH:33][CH:34]=[CH:35][N:36]=1)[CH2:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29]
Reactant: CC(=O)OC(CC(CCC(C)(C)O)c1ncc[nH]1)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(O)CCC(CC(O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)c1ncc[nH]1
Reaction time: 2 h
Yield: 109.1 %

Procedure:
To a solution of acetic acid 1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hydroxy-3-(1H-imidazol-2-yl)-6-methyl-heptyl ester (32 mg, 0.058 mmol) in methanol (1 mL) was added potassium carbonate (100 mg, 0.724 mmol). The resulting solution was stirred for 2 hours then concentrated. The crude product was dissolved in a mixture of methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (32 mg, >100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1I)[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25](B(O)O)=[C:24]([O:32][CH3:33])[CH:23]=1>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:25]1[CH:26]=[C:27]([F:28])[C:22]([F:21])=[CH:23][C:24]=1[O:32][CH3:33])[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester and (example 85, intermediate c) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (79%). MS (ESI): m/z=419.139 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[CH:30]=[C:29]([CH3:31])[O:28][N:27]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1cc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: Cc1cc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine (D8) and 2'-methyl-4'-(5-methylisoxazol-3-yl)biphenyl-4-carboxylic acid (D83) using a procedure similar to that of Example 1 (75%) m.p. 197-9° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][CH2:13][O:12][CH3:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COCCN
Product: COCCNc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
One heats to reflux for 15 hours 0.3 mole of parachloronitrobenzene (47.35 g) in solution in 150 ml of β-methoxyethylamine. One then pours the cooled reaction mixture into 300 g of crushed ice. The intended product precipitates first in the form of a red oil which crystallizes rapidly. After recrystallization in ethanol and drying under vacuum the product melts at 86° C. Analysis gives the following results: