Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.B(F)(F)F.CCOCC.O>C1C=CC=CC=1>[C:5]1([C:1]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: C1CCNC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CC=C(c1ccccc1)N1CCCC1
Yield: 78.9 %

Procedure:
In 50 ml of benzene, 9.38 g of propiophenone, 14.93 g of pyrrolidine and 0.99 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 67 hours using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent under a reduced pressure, the residue was subjected to a distillation under a reduced pressure to obtain 10.33 g of the desired enamine (yield: 79%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=O)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[S:28])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: FC(F)(F)c1ccc2c(c1)C1CCCC1C(=S)N2
Yield: 61.4 %

Procedure:
Analogously to Example 4, 8-(trifluoromethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (0.15 g, 0.6 mmol) is reacted with Lawesson's reagent (0.49 g, 1.2 mmol) to form 0.10 g (61%) of product.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12](O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[CH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CC=CC(=O)O1

Procedure:
6-t-Butyldimethylsilyloxymethyl-4-hydroxytetrahydropyran-2-one (1.0 parts) was dissolved in toluene and p-toluenesulphonic acid (0.1 parts) was added. The reaction mixture was heated at reflux with removal of water via a Dean and Stark apparatus. The cooled reaction mixture was then washed with water and evaporated to give 6-t-butyl dimethylsilyloxymethyl-5,6-dihydropyran-2-one (0.3 parts).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8](CC=C)[CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].C1([SiH3])C=CC=CC=1.C(O)(=O)C>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20]
Reactant: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]cnc21

Procedure:
1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.45 g, 1.63 mmol), phenylsilane (0.25 ml, 2.03 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.3 mmol) was dissolved in DCM (10 ml) containing acetic acid (6 ml). The air in the flask was replaced by nitrogen by evacuating the flask then filling with nitrogen (×3) and the reaction mixture heated to 45 C for 4 h. The solution was allowed to cool diluted with DCM then washed with water then saturated sodium bicarbonate solution. The organics were isolated, dried and concentrated to yield crude product. Purification by SPE (silica) eluting with ether provided the product, 0.06 g, 16%. m/z 237 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Br:15])[CH:3]=[C:2]([NH2:1])[CH:7]=1)=[O:9]
Reactant: COC(=O)c1cc(N)cc(B(O)O)c1
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(N)cc(-c2ccccc2Br)c1
Temperature: 90 °C
Yield: 75.6 %

Procedure:
A mixture of (3-amino-5-methoxycarbonylphenyl)boronic acid (1.02 g, 5.23 mmol), 1,2-dibromobenzene (2.47 g, 10.46 mmol), potassium carbonate (5.52 g, 40 mmol) and tetrakis(triphenylphosphine)palladium(0) (606 mg, 0.523 mmol) in 1:1 toluene/ethanol (30 ml) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was purified using Biotage with ethyl acetate/iso-hexane (3:17) to yield the title compound as a colourless gum (1.21 g, 76%).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([O:13][C:14]([CH:16]([O:23]/[N:24]=[C:25](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[S:45][CH:46]=1)\[C:26]([O:28]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[C:9]([O:13][C:14]([CH:16]([O:23]/[N:24]=[C:25](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[S:45][CH:46]=1)\[C:26]([OH:28])=[O:27])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)C(O/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1ccccc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1ccccc1
Temperature: -30 °C
Yield: 56.2 %

Procedure:
To a mixture of 4 ml of methylene dichloride and 1 ml of anisole was added 2.61 g (0.0033 mole) of benzhydryl (Z)-2-(α-tert-butoxycarbonylbenzyloximino)-2-(2-tritylaminothiazol-4-yl)acetate and after cooling the mixture to -30° C., 3 ml of trifluoroacetic acid was added dropwise to the mixture at a temperature below -20° C. over a period of 5 minutes. Thereafter, the mixture was maintained for one hour at -20° C. to -15° C. and then, methylene dichloride and trifluoroacetic acid were distilled off at low temperature under reduced pressure to provide an oily product. The oily product was subjected to silica gel column chromatography, eluted with a mixture of chloroform, isopropyl alcohol, and formic acid (90:10:2), the fractions containing the desired product were collected, and the solvents were distilled off to provide 1.15 g (Z)-(α-tert-butoxycarbonylbenzyloximino)-2-(2-tritylaminothiazol-4-yl)acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:46][C:47]([F:62])([F:61])[C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=2)=[CH:50][CH:49]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:13][C:57]2[CH:56]=[CH:55][C:54]([C:51]3[CH:52]=[CH:53][C:48]([C:47]([F:46])([F:61])[F:62])=[CH:49][CH:50]=3)=[CH:59][CH:58]=2)[CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCC(O)c1ccc(C(=O)OC)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-propyl)-benzoic acid methyl ester (300 mg, 1.55 mmol) in toluene (10 mL) is added 1, 1′-(azodicarbonyl)dipiperidine (ADDP, 585 mg, 2.32 mmol) at 0° C., followed by the addition of tributylphosphine (0.58 mL, 2.32 mmol) and 4′-trifluoromethyl-biphenyl-4-ol (442 mg, 1.86 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 hours at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (570 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[C:3]1[CH3:14].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([CH2:36][C:37]([O:39]CC)=[O:38])=[CH:31][C:30]=1[Cl:42].C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+].Cl>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:42][C:30]1[C:29]([NH:28][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:14])=[O:13])=[CH:34][C:33]([F:35])=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:31]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2cc(F)c(CC(=O)O)cc2Cl)c2ccccc2n1C
Temperature: 0 °C
Yield: 50.3 %

Procedure:
In methylene chloride (8 ml) was dissolved 1,2-dimethyl-1H-indole-3-carboxylic acid (270 mg, 1.43 mmol) was dissolved. Oxalyl chloride (0.19 ml, 2.1 mmol) was added to the solution under stirring at 0° C. The reaction mixture was stirred at room temperature for 1 hour and distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (6 ml) and the resulting solution was added to a solution of triethylamine (0.56 ml, 4.3 mmol) and ethyl (4-amino-3-chloro-6-fluorophenyl)acetate (331 mg, 1.4 mmol) in methylene chloride (3 ml) under stirring at 0° C. The reaction mixture was heated at reflux for 18 hours. HOBt (catalytic amount) was added to the reaction mixture and the mixture was heated under reflux for 48 hours. After cooling, the reaction mixture was added with chloroform and a saturated aqueous solution of citric acid. The mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 9:1 to 7:3, 20 ml/min, φ 50 mm×150 mm, dry silica gel adsorption method). The purified product was dissolved in THF (15 ml) and to the resulting solution was added 0.25M NaOH (8.6 ml, 2.2 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 1M HCl to acidify therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (5-chloro-2-fluoro-4-((1,2-dimethyl-1H-3-indolylcarbonyl)amino)phenyl)acetic acid (264 mg, 49%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].[OH-:22].[Na+].OO>C1COCC1.C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH2:10][CH:11]([OH:22])[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [OH-]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC(O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of borane dimethyl sulphide complex (7.38 mL) was added to an ice cooled, stirred solution of methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 12, 7.49 g) in anhydrous THF (100 mL) and the mixture was stirred at room temperature for two hours. The resulting mixture was cooled in an ice bath and water (2.6 mL) was added carefully followed successively by 3M sodium hydroxide (31 mL) and 50% hydrogen peroxide (16 mL). After stirring vigorously at room temperature for 45 minutes, the mixture was diluted with ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-60% to give methyl 7-(2,2-dimethylpropionylamino)-3-hydroxychroman-8-carboxylate (3.46 g) as a white foam.
Reaction SMILES: [C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:51]([O:58][C:59]([N:61]1[CH2:65][CH:64]([C:66]2[C:74]3[C:69](=[CH:70][C:71]([F:75])=[CH:72][CH:73]=3)[NH:68][CH:67]=2)[CH:63]2[N:76]([C:79](=[O:89])[CH:80]([NH2:88])[CH:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])[CH3:82])[CH2:77][CH2:78][CH:62]12)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:51]([O:58][C:59]([N:61]1[CH2:65][CH:64]([C:66]2[C:74]3[C:69](=[CH:70][C:71]([F:75])=[CH:72][CH:73]=3)[NH:68][CH:67]=2)[CH:63]2[N:76]([C:79](=[O:89])[CH:80]([NH:88][C:14](=[O:16])[CH:12]([N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH3:17])[CH3:13])[CH:81]([O:83][C:84]([CH3:86])([CH3:85])[CH3:87])[CH3:82])[CH2:77][CH2:78][CH:62]12)=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(OC(C)(C)C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(OC(C)(C)C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution containing Cbz-N(Me)Ala-OH (119 mg, 0.5 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (189 mg, 0.5 mmol) and DIPEA (111 mg, 0.8 mmol) were added followed by the addition of crude 44 (280 mg, 0.5 mmol) in anhydrous NMP (4 mL). The reaction mixture was slowly warmed to ambient temperature. After 2 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 330 mg of crude 45 as an amber-colored oil which was used without further purification. Mass spectrum, m/z [756.4] (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH2:42][CH3:43])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH2:42][CH3:43])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 63.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (840 mg, 2.7 mmol) was reacted with tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (1.5 g, 4.0 mmol) to afford the desired product (820 mg, 43%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.C(O)C.[OH-].[Na+]>O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
1-(5-Bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.1 g) was added to ethanol (20 ml), water (10 ml) and 4N aqueous solution of sodium hydroxide (10 ml), stirred at 80° C. for five hours, and the solvent was evaporated in vacuo. 1N Hydrochloric acid aqueous solution was added to the residue at 0° C. and the precipitated solid was washed with water to give the titled compound (1.78 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([O:11][P:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])C>Cl[Ni]Cl>[CH2:14]([O:13][P:12]([C:2]1[CH:7]=[CH:6][C:5]([P:12]([O:13][CH2:14][CH3:15])(=[O:11])[O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1)(=[O:11])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: Brc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Product: CCOP(=O)(OCC)c1ccc(P(=O)(OCC)OCC)cc1
Temperature: 170 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
10 g (42 mmoles) of 1,4-dibromo-benzene and 600 mg of anhydrous NiCl2 are placed in a two-necked 250 ml flask which has a cooler, dripper funnel and magnetic agitation. 17.6 ml (100 mmoles) of triethyl-phosphite are added to the mixture dropwise and heated to 170° C. in an oil bath. The mixture is left under agitation at 170° C. for 2 hours, it is then cooled to 100° C. and subjected to vacuum distillation (1 mm Hg) to eliminate the excess triethyl-phosphite. The residue solubilized in 10 ml of ethanol undergoes chromatography on a silica column (5×56 cm) eluting first with 4 liters of a 95:5 ethyl-acetate/ethanol mixture and then with 3 liters of a 90:10 ethyl-acetate/ethanol mixture. 6.0 g (17.4 mmoles) of 1,4-benzene-diphosphonic acid tetra-ethyl ester are obtained with a molar yield of 41%.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[C:35]([O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:24][CH:25]=3)[C:20]([CH3:30])=[C:19]2[CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:14]Br>C(O)C>[Br:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)nn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
To a 250 mL round-bottomed flask was added 6-chloropyridazin-3-amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water, and the product extracted with ethyl acetate (3 times). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1A (4.5 g, 71.3% yield). HPLC: Rt=1.25 min (Waters Sunfire C18 column (4.6×50 mm). 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, flow rate=4 mL/min, detection at 254 nm). MS (ES): m/z=207.88 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[C:13]([CH3:18])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:12][C:13]=2[CH3:18])[CH:21]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Cc1cc(S(=O)(=O)c2ccc(F)cc2)ccc1Br
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1C

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Li]CCCC.[O:13]1[CH2:15][CH2:14]1>CCOCC>[Br:7][C:5]1[CH:6]=[C:2]([CH2:15][CH2:14][OH:13])[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OCCc1cc(Br)cs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in anhydrous ether was added n-BuLi (1.66 mL, 4.13 mmol) at −78° C. dropwise. After stirring at −78° C. for 0.5 hr, oxirane (0.32 mL, 19.28 mmol/mL in ether) was added to the reaction mixture quickly. After stirring at 0° C. for 1.5 hr, the reaction mixture was quenched with aqueous NH4Cl solution, extracted with EtOAc, concentrated and purified to give the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:28]([F:31])([F:30])[F:29])=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH:17]([NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH2:16][CH2:15]3)[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[OH:3][CH2:4][C:6]1[C:7]([C:28]([F:29])([F:31])[F:30])=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH:17]([NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH2:16][CH2:15]3)[CH:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc3c(c2)CCC3NS(=O)(=O)C(C)C)nc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl-1-((1-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoro methyl)-1H-pyrazole-4-carboxylate (0.196 mmol, 90 mg) was dissolved in THF (5 mL) and cooled in an ice bath under nitrogen. Di-isobutyl aluminium hydride (0.588 mmol, 0.588 mL) was added dropwise and the reaction stirred for 1.5 h. The reaction mixture was warmed to room temperature and stirred for a further 30 min before an additional 0.2 ml of di-isobutyl aluminium hydride was added and stirring continued for 30 min before quenching with MeOH followed by water. The mixture was concentrated before partitioning between EtOAc/water. The aq. layer was acidified with 5N HCl until all solids were in solution. The organic phase was collected, dried and concentrated and the residue purified by HPLC to give a colourless oil which crystallised on standing (63 mg, 0.151 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ 1.43 (d, 6H) 1.95 (m, 1H) 2.65 (m, 1H) 2.80 (m, 1H) 3.00 (m, 1H), 3.24 (m, 1H) 4.20 (d, 1H) 4.65 (s, 2H) 4.95 (q, 1H) 5.28 (s, 2H) 7.13 (m, 2H) 7.44 (m, 2H).