Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[N:17]=3)[C:12](=[O:20])[C:11]([C:21](O)=[O:22])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][O:26][CH3:27].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH3:27][O:26][N:25]([CH3:24])[C:21]([C:11]1[C:12](=[O:20])[C:13]2[C:18](=[N:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: CNOC
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(Cc3cccc(Br)n3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Yield: 79.5 %

Procedure:
0.667 mL (3.75 mmol, 50% solution in ethyl acetate) of 1-propanephosphonic anhydride solution was added to 0.400 g (1.07 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, 0.208 g (2.13 mmol) of N,O-dimethylhydroxyl amine, and 0.653 mL (3.75 mmol) of diisopropylethylamine dissolved in 1 mL of dichloromethane. After the reaction was stirred at room temperature for 1 hour water was added and was extracted with dichloromethane (3×25 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel eluting with 100% ethyl acetate to yield 0.355 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide as a white solid.
Reaction SMILES: [C:1]1([C:7]([S:10][CH2:11][CH2:12][OH:13])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(NC2C=CC(NC3C=CC=CC=3)=CC=2)C=CC=CC=1.[C:34](OCC)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([O:13][CH2:12][CH2:11][S:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])(=[O:37])[CH:35]=[CH2:36]
Reactant: CC(C)(SCCO)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=CC(=O)OCCSC(C)(C)c1ccccc1
Temperature: 120 °C

Procedure:
Into a 3-neck 250 mL round-bottomed flask were weighed, in the following order: 2-(2-phenylpropan-2-ylthio)ethanol (30.0 g, 0.1528 moles), N,N′-diphenyl-1,4-phenylene diamine (0.318 g, 1.2224×10−3 moles) and ethyl acrylate (122.40 g, 1.2224 moles). The apparatus was then assembled in a reactive distillation arrangement before being purged with N2 (g). The Claisen head of the distillation apparatus was wrapped with Al-foil/glass wool. The reaction flask was then heated to 120° C., by use of a silicone heating oil bath, and once the ethyl acrylate (Bpt: 99° C.) started to distil over tetrapropoxytitanate (TPT) (1.04 mL, 0.999 g, 3.5144×10−3 moles) was added to the reaction mixture via a 2.50 mL Hamilton gastight syringe. The distillation rate immediately increased significantly and the distillation vapour temperature decreased from 98° C. to ca. 80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CN(C=O)C.[Cu]I>[N:14]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]3)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2cc(-n3ccnc3)ccc2n1
Temperature: 150 °C
Yield: 77.9 %

Procedure:
6-bromo-2-methoxy-quinoline (19 g; 79.8 mmol; RN: 99455-05-7) was dissolved in dry DMF (100 mL), imidazole (5.7 g; 84 mmol), K2CO3 (11.6 g, 84 mmol), and CuI (1.1 g, 4.2 mmol) were added at r.t. under stirring and in argon atmosphere. The resulting mixture was heated at 150° C. for 48 hours. The reaction mixture was cooled at r.t. and poured into 2% (w/w) aqueous EDTA solution (600 mL), the resulting precipitate was filtered and washed with water, dried and then suspended in hexane/AcOEt. The resulting suspension was stirred for 10 min., filtered and the collected title product was dried, 14 g (yield 78%) of white crystals were obtained. C13H11N3O, MW: 225.25. MS (ESI) m/z: 226 (M+1). 1H-NMR (200 MHz, CDCl3) ppm: 3.6 (s, 3H), 6.97 (s, 1H), 7.51 (s, 1H), 7.82 (d, 1H), 8.10 (dd, 1H), 8.13 (d, 1H), 8.27 (s, 1H), 8.84 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1O[CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C.O.Cl.C[C:23]1[NH:24]C=C[C:27](=[O:37])[C:28]=1[O:29]CC1C=CC=CC=1>OCC(CO)O>[CH2:23]([N:24]1[CH:4]=[CH:5][C:6](=[O:16])[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]1[CH3:1])[CH:28]([CH2:27][OH:37])[OH:29]
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: OCC(O)CO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Yield: 40 %

Procedure:
35.6 g (165 mmol. 1.5 eq.) of 2-methyl-3-benzyloxy-4-pyranone and 10 g (110 mmol) of 1-amino-1-desoxy-glycerol are put into 600 mL of a 50:50 ethanol-water mixture; then 14 mL of an aqueous solution of soda (2N) is added. The reaction medium is then brought under reflux agitation for 48 hours. The reaction medium is left to cool, and then a solution of concentrated HCl is added to reach a pH=1. After evaporation of ethanol, the resifue is extracted using ethyl ether (3×100 mL) in order to eliminate any excess of 2-methyl-3-benzyloxy-4-pyranone. The aqueous phase is brought to neutral pH by addition of an aqueous solution of NaOH and then concentrated under reduced pressure. The residue is retaken up with a minimum of water. By precipitation, 12.7 g (43.9 mmol) of 2-methyl-3-benzyloxypyridine-4(1H)-one of glycerol is isolated, which is pure at chromatographic and NMR analyses. Yield 40%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C1COCCN1
Product: Brc1ccc2nccc(N3CCOCC3)c2c1

Procedure:
122 mg 6-bromo-4-chloroquinoline and 0.13 mL morpholine were reacted by the same method as in Production Example 74 to give 68 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:18]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[N:7]=[C:2]([CH3:1])[CH:3]=1)=[O:20]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1cc(C(=O)O)c2cnn(Cc3ccccc3)c2n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(Cc3ccccc3)c2n1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (200 mg, 0.748 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (142 mg, 0.935 mmol), 1-hydroxy-7-azabenzotriazole (204 mg, 1.497 mmol), DMSO (10 mL), EDC (287 mg, 1.497 mmol), and N-methylmorpholine (0.329 mL, 2.99 mmol). The final product was collected as 0.25 g (83%). LCMS E-S (M+H)=402.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.12 (m, 4 H), 1.42 (d, J=6.82 Hz, 6 H), 2.12 (s, 3 H), 2.22 (s, 4 H), 2.36 (s, 3 H), 4.34 (d, J=4.80 Hz, 2 H), 4.90-5.11 (m, 1 H), 5.87 (s, 1 H), 6.99 (s, 1 H), 8.58 (s, 1 H), 11.51 (s, 1 H.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([Cl:20])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CN>Cl.CC(O)=O.CO.O.CCN(CC)CC>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([Cl:20])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2nc(NC(=O)NC3CCCCC3)cnc21
Agent: Cl
Solvent: O
Solvent: CO
Solvent: NCCN
Product: O=C(Nc1cnc2[nH]cc(Cl)c2n1)NC1CCCCC1
Temperature: 50 °C
Reaction time: 120 h
Yield: 16.4 %

Procedure:
1-Cyclohexyl-3-[7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (44 mg, 0.104 mmol) was dissolved in a solution of HCl in AcOH (1M, 2.1 mL), and heated at 50° C. in the sealed tube overnight. The reaction mixture was concentrated to dryness, dissolved in 1 mL of MeOH:H2O:Et3N 8:1:1 and ethylenediamine (69 ul, 1.04 mmol) was added. The reaction mixture was stirred for 5 days, concentrated and purified by SiO2 chromatography (8 g SiO2, DCM/MeOH 0 to 10% MeOH) to give 5 mg of 1-cyclohexyl-3-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as a white solid (16% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[C:20]4[N:21]=[CH:22][CH:23]=[CH:24][C:19]=4[C:18]4=[N:25][NH:26][C:27](=[O:28])[C:17]4=[N:16]3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[F:47][C:48]1[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][C:49]=1I.C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cu]I>[F:47][C:48]1[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][C:49]=1[N:26]1[C:27](=[O:28])[C:17]2=[N:16][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[N:9][CH:10]=3)[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]2=[N:25]1
Reactant: Cc1cccc(I)c1F
Reactant: Cc1ccc(-c2ccc(Cn3nc4c(=O)[nH]nc-4c4cccnc43)cn2)cn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n(-c5cccc(C)c5F)nc-4c4cccnc43)cn2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5-[(6′-Methyl-2,3′-bipyridin-5-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazine-3-one (40 mg, 0.11 mmol), copper(I) iodide (21 mg, 0.11 mmol, 1 equiv), potassium phosphate (0.14 g, 0.65 mmol, 6 equiv), (±)-trans-N,N′-bismethyl-1,2-cyclohexanediamine (46 mg, 0.32 mmol, 3 equiv) and 2-fluoro-1-iodo-3-methylbenzene (64 mg, 0.27 mmol, 2.5 equiv) were combined in degassed N,N-dimethylformamide (2.5 mL) and placed into an oil bath preheated to 110° C. for 45 min. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed once with brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 10% methanol), providing the titled compound as a red solid: 1H-NMR (400 MHz, CDCl3) δ 9.04 (1H, d, J=1.8 Hz), 8.97 (1H, d, J=1.7 Hz), 8.79 (1H, dd, J=4.6, 1.9 Hz), 8.56 (1H, dd, J=8.0, 1.8 Hz), 8.18 (1H, dd, J=8.1, 2.2 Hz), 8.01 (1H, dd, J=8.2, 2.3 Hz), 7.70 (1H, dd, J=8.2, 0.6 Hz), 7.52 (1H, dd, J=8.0, 4.6 Hz), 7.41-7.37 (1H, ), 7.27-7.22 (2H, m), 7.15 (1H, ap t, J=7.9 Hz), 6.01 (2H, s), 2.60 (3H, s), 2.36 (1H, J=2.0 Hz) ppm; high resolution mass spectrometry (ES+) m/z 478.1783 [(M+H)+; calculated for C27H21FN7O: 478.1786].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=3[C:10]([F:13])([F:12])[F:11])=[CH:25][CH:24]=2)=[CH:31][CH:32]=1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a stirred solution of the 4-fluoro-3-(trifluoromethyl)benzaldehyde (177 μL, 1.30 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (359 mg, 1.30 mmol) in DMSO (3 ml) was added K2CO3 (270 mg, 1.95 mmol). The reaction was stirred at 95° C. for 2 hours and then directly purified by silica gel chromatography to give N-(4-chlorophenethyl)-4-(4-formyl-2-(trifluoromethyl)phenoxy)benzamide (0.541 g).
Reaction SMILES: Cl.[CH:2]1([CH:5]([NH2:9])[CH:6]2[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#[N:11]>CCCCCCCCCC.C1(C)C=CC=CC=1>[CH:2]1([CH:5]([NH:9][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[NH:11])[CH:6]2[CH2:8][CH2:7]2)[CH2:4][CH2:3]1
Reactant: N#CNC(=N)N
Reactant: NC(C1CC1)C1CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCC
Product: N=C(N)NC(=N)NC(C1CC1)C1CC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
1.6 g (10.8 mmol) of 1,1-dicyclopropylmethylamine hydrochloride were admixed with 0.91 g (10.8 mmol) of cyanoguanidine in a mixture of 6 ml of decane and 20 ml of toluene. The mixture was heated to a temperature of 140° C. for 5 h, in the course of which toluene distilled off. The flask contents were cooled to room temperature, then acetone was added. The precipitate was decanted off and freed of residual solvent under reduced pressure. 1.7 g of the crude product (purity approx. 80%) were obtained, which were used for the next synthesis stage without further purification.
Reaction SMILES: C[C@@H:2]([OH:34])[C@H:3]1[O:8][C@H:7]([O:9][C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H:6](N)[C@@H:5]([OH:32])[C@@H:4]1[OH:33].C([OH:39])C(C)C>>[O:9]=[CH:7][C@@H:6]([C@H:5]([C@@H:4]([C@@H:3]([CH2:2][OH:34])[OH:8])[OH:33])[OH:32])[OH:39]
Reactant: CC(C)CO
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)O)[C@@H](O)[C@H](O)[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
Strains with integrated ALS genes expressed from the CUP1 promoter were transformed with pGV2082 (which carries the other 4 isobutanol pathway genes Ec_ilvC_coScQ110V (SEQ ID NO: 61), Ll_ilvD (SEQ ID NO: 65), Ll_kivd2_coEc (SEQ ID NO: 59), and Dm_ADH (SEQ ID NO: 60)). Strains were patched onto YPD plates containing 0.2 mg/mL G418. The following morning cells were removed from the plate with a sterile toothpick and resuspended in 4 mL of YPD with 0.2 mg/mL G418. The OD600 was determined for each culture. Cells were added to 50 mL YP with 5% dextrose and 0.2 mg/mL G418 such that a final OD600 of 0.1 was obtained. 1 mL of media was removed and the OD600 for this undiluted sample determined, leftover media was stored at 4° C. to act as media blank for the analytics submission, and to act as the t=0 sample for the fermentation. At t=24 h, 2 mL of media was removed and 25 μL used at a 1:40 dilution to determine OD600. The remaining culture was centrifuged in a microcentrifuge at maximum speed for 10 min and a 1:10 dilution read on the YSI. 50% glucose containing 0.2 mg/mL G418 was added to a final concentration of 100 g/L glucose. 1 mL of supernatant was analyzed by gas chromatography as described above. At t=48 h, 2 mL of media was removed and 25 μL used at a 1:40 dilution to determine OD600. The remaining culture was centrifuged in a microcentrifuge at maximum speed for 10 min and a 1:10 dilution read on the YSI. 50% glucose plus water (with 0.2 mg/mL G418) were added to give a final concentration of glucose of 100 g/L. 1 mL of supernatant was analyzed by gas chromatography. At t=72 h, 2 mL of media was removed and 25 μL used at a 1:40 dilution to determine OD600). The remaining culture was centrifuged in a microcentrifuge at maximum speed for 10 min and a 1:10 dilution read on the YSI. 1 mL of supernatant was analyzed by gas chromatography and high performance liquid chromatography.
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])([OH:3])=[O:2]>C(O)CCC=C>[CH2:1]([O:22][C:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:1]([O:3][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9])=[O:2])=[O:24])=[O:23])[CH2:4][CH2:8][CH:7]=[CH2:6]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Agent: C=CCCCO
Product: C=CCCCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCCCC=C
Temperature: 25 °C
Reaction time: 48 h
Yield: 111.9 %

Procedure:
A mixture of 2.04 g (6 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid and 5 g Amberlite® IR120 in 25 ml 4-penten-1-ol were stirred at room temperature for 48 hours. After filtration the solvent was distilled off, the residue was taken up in dichloromethane and extracted with 2% aqueous sodium bicarbonate. The organic extract was dried with sodium sulfate and the solvent was distilled off to yield 1.6 g (58%) (R)-1-[6-[(R)-2-pent-4-enyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid pent-4-enyl ester as a light yellow oil, MS m/e (%): 477 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[S:13]1[C:17](B(O)O)=[CH:16][C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]1=2.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C(O)C.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>[N+:9]([C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:17]2[S:13][C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[CH:16]=2)=[C:3]([CH3:12])[CH:4]=1)([O-:11])=[O:10]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1-c1cc2ccccc2s1

Procedure:
A mixture of 2-bromo-5-nitro-p-xylene (200 g), 2-benzo[b]thiopheneboronic acid (200 g), (Ph3P)4Pd (0.36 g) in toluene (60 ml) and ethanol (22 ml) was heated to reflux overnight. Ethyl acetate and water were added and the organic phase was separated. The organic phase was washed with water, dried (MgSO4) and filtered through a pad of silica to give the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].C(N(CC)CC)C.[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 73 %

Procedure:
Into 200 mL methylene chloride was dissolved 10.45g (50 mmol) 2-aminoterephthalic acid dimethyl ester. The solution was cooled in an ice bath, and 7.73 mL (55 mmol) triethylamine was added, followed by 10.76 mL 4-tert-butylbenzoyl chloride in 50 mL methylene chloride dropwise. The mixture was allowed to come slowly to room temperature, and after 16 h the mixture was shaken with 200 mL cold dilute HCl and 200 mL satd NaHCO3. The organic layer was dried (MgSO4) and evaporated. The residue was redissolved in a minimum ether, giving 13.5 g (73%) of crystalline desired intermediate.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:18](=O)[CH3:19])[C:3]=1[O:21][CH:22]([CH3:24])[CH3:23].[CH3:25][CH2:26][O:27][C:28]([CH:30](P(OCC)(OCC)=O)[F:31])=[O:29].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:19])=[C:30](/[F:31])\[C:28]([O:27][CH2:26][CH3:25])=[O:29])[C:3]=1[O:21][CH:22]([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-tert-butyl-3-isopropoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-115, 143 mg, 0.36 mmol) and triethyl 2-fluoro-2-phosphonoacetate (352 mg, 1.46 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 0.91 mL, 1.46 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.7 %

Procedure:
To a stirred solution of 4-bromo-3-methylaniline (3.32 g, 17.8 mmol) in dry dichloromethane (150 ml) was added triethylamine (4.96 ml, 35.6 mmol), followed by methanesulphonyl chloride (1.52 ml, 19.6 mmol). The complete reaction mixture was stirred at room temperature under Ar for 18 hours. The mixture was then washed with water, saturated potassium carbonate solution, and finally brine. The organic layer was dried (Na2SO4) and concentrate din vacuo to afford a creamy orange solid. This was dissolved in dichloromethane and shaken with 10% sodium hydroxide solution. The aqueous layer was separated and acidified to pH 6 using concentrated hydrochloric acid. This solution was then extracted using chloroform. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (1.35 g, 30%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([O:17][CH3:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:20]O>>[CH3:20][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[O:17][CH3:18]
Reactant: COc1cc(C2CCCCC2)ccc1CC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(C2CCCCC2)cc1OC
Reaction time: 18 h

Procedure:
A solution of 20 g of (4-cyclohexyl-2-methoxyphenyl)-acetic acid in 200 ml of dry methanol is saturated with HCl gas at 0°. After standing at 22° for 18 hours, it is evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCSc1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCSc1cccc(Br)c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
A solution of ethyl 3-[(3-bromophenyl)thio]propanoate (1.15 g) in ethanol (5 ml) was treated with aqueous sodium hydroxide solution (2M, 5 ml) and the mixture was stirred at 20° C. for 15 h. The mixture was acidified with hydrochloric acid and the solution was extracted with ethyl acetate. The organic solution was washed with hydrochloric acid, brine, dried (MgSO4), and evaporated to give the title compound (390 mg) LCMS RT=3.19 min