Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29]1)[N:22]=2)[C:14]#N.C(C(C(C([O-])=O)O)O)([O-])=[O:38]>C(Cl)Cl>[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29]1)[N:22]=2)[CH:14]=[O:38]
Reactant: Cc1cc(C#N)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (11.0M in hexanes; 0.315 mL, 0.315 mmol) was added to a solution of 3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile (105.2 mg, 0.286 mmol) in CH2Cl2 (4.5 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Additional DIBAL-H (1.0M in hexanes; 86 μL, 86 μmol) was then added, and the resulting solution was stirred at 25° C. for 30 min. Saturated aqueous Na/K tartrate solution (4.0 mL) was added, and the resulting mixture was vigorously stirred for 15 min, then partitioned between CH2Cl2 (40 mL) and saturated aqueous Na/K tartrate solution (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) provided 3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light-yellow foam. MS (ESI) m/z: Calculated: 370.1; Observed: 371.1 (M++1).
Reaction SMILES: [CH:1](OCC)=[O:2].C[O-].[Na+].[CH:9]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]>C(OCC)C>[CH:9]([CH:12]1[CH2:17][CH:16]([CH:1]=[O:2])[C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C1CCC(=O)C(C=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl formate (6 mmol) in diethyl ether (2 ml) was added dropwise to a suspension of sodium methoxide (6 mmol) and 4-isopropyl-cyclohexanone (3 mmol) in absolute diethyl ether (3 ml) and after complete evolution of the gas the reaction mixture was stirred overnight at room temperature. The solid formed was filtered off, washed with diethyl ether and dried in a high vacuum. The product was obtained as a slightly yellow solid. tR 2.26; MS (pos. Ion.) m/z 169.32 [M+H]+. (J. Org. Chem. 2000, 65(21), 7145-7150).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([CH3:16])[CH3:15]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(C)N
Product: CC(C)N[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and isopropylamine. Melting point: 61°-63° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(F)ccc1F
Product: Nc1ccc(C(=O)c2cc(F)ccc2F)cc1
Reaction time: 1 h
Yield: 209.6 %

Procedure:
To stirred 90° C. polyphosphoric acid (125 g) was added 2,5-difluoro-benzoic acid (10.0 g, 6.32 mmol) and aniline (5.87 g 6.3 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 50 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 45 mL of 3N HCl added, the mixture poured into 650 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the mixture filtered through a pad of Celite. The Celite pad was washed well with methylene chloride, the methylene chloride dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash column chromatography (methylene chloride) followed by recrystallization twice from 50% ethanol (80 mL) yielded the aniline as a yellow solid (3.08 g, 21%); mp 101°-103° C. 1H-NMR (300 MHz, CDCl3): 4.27 (s, 2H, NH2) 6.63-6.67 (m, 2H, aromatic) 7.09-7.19 (m, 3H, aromatic) 7.68-7.71 (m, 2H, aromatic). MS (CI, CH4): 234 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[C:23]([CH3:29])=[N:24][C:25](Cl)=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[C:23]([CH3:29])=[N:24][C:25]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Reactant: C1COCCN1
Product: Cc1nc(N2CCOCC2)ccc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Yield: 58 %

Procedure:
A solution of 4-[6-(6-chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (613 mg, 1.46 mmol) in 15 mL morpholine was reacted under microwave irradiation at 180° C. for 14 hours. Mixture was concentrated and purified by HPLC to give Compound A91 as a white solid (427 mg, 58%). 1H NMR (MeOH-d4, 400 MHz) δ 1.03-1.05 (d, 6H), 1.51-1.60 (m, 2H), 1.78-1.85 (m, 2H), 1.98 (s, 3H), 2.29 (s, 3H), 3.19-3.25 (m, 2H), 3.54-3.58 (m, 6H), 3.65-3.67 (m, 4H), 4.65-4.70 (m, 1H), 5.20-5.25 (m, 1H), 7.08-7.10 (d, 1H), 7.68-7.71 (d, 1H), 8.07 (s, 1H). Exact mass calculated for C24H34N6O4 470.26, found 471.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH3:25][N:26]1[CH:30]([CH3:31])[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][CH2:27]1>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:27][N:26]([CH:30]([CH3:31])[CH:29]([OH:28])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:25])[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: CC1C(c2ccccc2)OCN1C
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CN(C)C(C)C(O)c3ccccc3)c(O)c(OC)c1)O2
Yield: 29.5 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofuran and 21.3 g of 3,4-dimethyl-5-phenyl-1,3-oxazolidine are held in 200 ml of absolute alcohol for 60 hours at 70° C. and subsequently the solvent and excess 3,4-dimethyl-5-phenyl-1,3-oxazolidine are removed, finally in vacuum. After purification by means of a chromatographic column there is obtained 9.1 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenylmethyl)-N-(1-hydroxy-1-phenyl-2-propyl)-N-methylamin, a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([OH:25])[CH:6]=1)=[O:4].[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](O)=[CH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35]2)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([O:25][C:32]2[C:31]3[C:36](=[CH:37][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:35]=[C:34]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[CH:6]=1)=[O:4]
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To an ice cooled solution of 29 (41 mg, 116 mmol) in dry THF, 7-methoxy-2-phenyl-quinolin-4-ol (150 mmol) and triphenylphosphine (150 mmol) were added. Then DIAD (160 mmol) was dissolved in THF (2 mL) and added dropwise to the solution. After one hour the mixture was concentrated and purified using flash chromatography (toluene/ethyl acetate 3:1). This gave the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si](C)(C)C)=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)#[CH:9]
Reactant: Cc1ccc(C#C[Si](C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C)cn1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To the solution of 5-methyl-2-((trimethylsilyl)ethynyl)pyridine (12-1) (4.16 g, 22 mmol) in THF was added tetra-n-butylammonium fluoride (44 mL, 44 mmol) at rt and the solution was stirred for 1 h. The solvent was removed under reduced pressure. The residue was purified by silca gel chromatography with eluent of PE/EA (20/1). The product was obtained as yellow oil (1.78 g, 69%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 3.10 (s, 1H), 2.35 (s, 3H); LRMS (ES) calculated M+H for C8H8N, 118.2. Found: 118.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([NH:22][CH2:23][CH:24](O)[CH2:25][CH3:26])[N:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:12]([N:22]2[CH2:23][CH:24]([CH2:25][CH3:26])[O:8][CH:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=1
Reactant: O=Cc1ccccn1
Reactant: CCC(O)CNc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1CN(c2cc(C(F)(F)F)c(C#N)c(Cl)n2)C(c2ccccn2)O1

Procedure:
Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-(2-hydroxybutylamino)-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg, 1.3 mmol) followed by a catalytic amount of para-toluene sulfonic acid (50 mg). The reactants were refluxed for 6 hours in a Dean-Stark apparatus, concentrated under reduced pressure, adsorbed onto silica and purified using a neutral alumina column, eluting with a mobile phase of 10% ethyl acetate in hexane. 2-Chloro-6-[5-ethyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 17) was isolated as a solid in 37% yield. mp 115-118° C.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:37])[CH:6]1[CH2:38][CH3:39])C=C.[Cl:40]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:40][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:37])[CH:6]1[CH2:38][CH3:39]
Reactant: ClCl
Reactant: C=CCSC1C(CC)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccccc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccccc2)C(=O)C(C)(C)C)C1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a solution of 2.47 g 4-nitrobenzyl 2-(4-allylthio-3-ethylazetidin-2-on-1-yl)-3-phenoxy-3-trimethylacetylthiopropenate in dichloromethane at -20° was added a solution of 8.4 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethane acetate mixtures afforded 1.782 g of the title compound as a pale yellow foam (78% of the theoretical yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.3 g, 0.858 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.355 g, 1.029 mmol) according to the general procedure VI. Obtained as a white solid (0.220 g, 48%). MS (ISP) 533.2 [(M+H)+]; mp 242° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:11]=[CH:10]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-6-hydroxynaphthalene (243 mg, TCI) in anhydrous THF (10 ml) was cooled to −78° C., added dropwise with a 1.6 M solution of n-butyllithium in hexane (1.18 ml) over 20 minutes under argon gas atmosphere, and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (1.73 ml) over 10 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 2 hours. The reaction mixture was added with 0.5 M aqueous sulfuric acid (2 ml), and extracted with diethyl ether (40 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 6-hydroxy-2-naphthaleneboronic acid (378 mg). A solution of this substance in ethanol (1 ml), Compound No. A-1 (230 mg), and 2 M aqueous sodium carbonate (2.4 ml) were added with toluene (3 ml) and (Ph3P)4Pd (115 mg) and stirred at 100° C. for 13 hours. The reaction mixture was added with ethyl acetate (100 ml), and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. V-3, 270 mg).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=O)C.[CH2:26]([NH2:29])[C:27]#[CH:28]>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:3])[N:29]([CH2:26][C:27]#[CH:28])[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:16])=[O:17])=[CH:23][CH:22]=1
Reactant: C#CCN
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Product: C#CCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)CC1=O

Procedure:
A title compound was prepared by the same method as in Example 4, except that it was prepared from the compound of Example 3 and propargylamine, and recrystallized with CH3Cl/hexane to obtain a white solid (yield 90%).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[C:16]([F:21])[CH:15]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(Br)ccc1-c1cc2ccccc2s1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A mixture of Benzo[b]thiophene-2-boronic acid (0.71 g, 4 mmol), 1-bromo-3-fluoro-4-iodobenzene (1 g, 3.3 mmol), bis(triphenylphospine)palladium(II) chloride (46 mg, 2 mol %), NaHCO3 (0.83 g, 9.9 mmol) in DME (4 mL) and H2O (4 mL) was heated to 80° C. under N2 for 72 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.13 g, 13%). 1H NMR (CDCl3): δ 7.33-7.41 (m, 4H), 7.57 (m, 1H), 7.72 (s, 1H), 1.80-7.86 (m, 2H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.N1C=CC=CC=1.C[OH:20]>>[C:1]([OH:7])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:20])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(O)CCCC(=O)O
Temperature: 80 °C
Yield: 97.6 %

Procedure:
Glutaric acid-terminated PEG (P8G) was synthesized by dissolving 8-arm PEG-OH (20 g, 7.97 mmol OH or 1 equivalent OH) and glutaric anhydride (4.54 g, 39.84 mmol, or 5 equivalents) in chloroform (2.5 mL chloroform per 1 mmol OH). Pyridine (5 eq) was added dropwise, and the reaction mixture was refluxed at 80° C. for 24 hours under inert air. The product was diluted with MeOH (240 mL or 12 mL MeOH per gram of PEG), precipitated at −20° C. for 1 hour, and centrifuged at −5° C. The supernatant was discarded, and the MeOH wash procedure was repeated twice more. Following diethyl ether precipitations (180 mL or 9 mL ether per gram of PEG), the product was dried under high vacuum overnight to afford a white powder (97.6% yield, 100% conversion). See FIG. 21.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: Cc1cccc(C=O)c1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cccc(C=CC(=O)O)c1[N+](=O)[O-]
Yield: 64 %

Procedure:
3-Methyl-2-nitrobenzaldehyde, prepared according to Berichte, 47, 406, is reacted with malonic acid in pyridine with the addition of piperidine to give 3-methyl-2-nitrocinnamic acid; yield 64% of theory; m.p. 230°-235° C., after recrystallisation from methanol. After hydrogenation thereof in aqueous sodium hydroxide solution in the presence of palladium catalyst, 2 mole of acetic anhydride are added thereto and the reaction product is purified on an Amberlite IR-120 column (H+ form). There is thus obtained, in a yield of 75% of theory, 3-(2-acetylamino-3-methyl-phenyl)-propionic acid; m.p. 110° C. sinters, 117°-120° C. This is then reacted with phosphorous acid/phosphorus trichloride analogously to Example 16.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]C(O)=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3]([CH:2]2[CH2:33][CH:32]2[C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:31][CH:30]=2)=[O:4])[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
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: ClCCl
Product: O=C(C1CC1c1ccc(C(F)(F)F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.086 g, 0.27 mmol) and 3-(4-(trifluoromethyl)phenyl)propanoic acid (60 mg, 0.27 mmol) in dry DCM (20 mL), DIPEA (72 mg, 1.37 mmol) followed by HATU (208 mg, 0.55 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound AGI-604 (0.118 g, 90.07%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:9]=1>CO.C(OCC)(=O)C.[Pd]>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:27])=[CH:9][C:10]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: COC(=O)/C=C/c1ccc(OCCCC(=O)OC)cc1OCCCCCO
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCOc1ccc(CCC(=O)OC)c(OCCCCCO)c1

Procedure:
A 2.0 g (5.26 mmol) sample of (E)-4-[3-[(5-hydroxypentyl)oxy]-4-(3-methoxy-3-oxo-1-propenyl)phenoxy]butanoic acid methyl ester was hydrogenated in 100 mL of 1:1 methanol-ethyl acetate, over 0.1 g of 10% palladium on carbon, at room temperature and 1 atmosphere. 2-[(5-Hydroxypentyl)oxy]-4-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester, an oil, was isolated by filtration of the catalyst and concentration of the filtrate, in quantitative yield.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4].[O:17]1C[CH2:20][CH2:19][CH2:18]1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: C1CCOC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part B) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of (E,E)-farnesyl chloride (Part A) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether : hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield a yield of 610.5 mg (58%) of pure desired title isomer.