Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)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:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1cnc2ccnn2c1
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: CCOCC
Solvent: CS(C)=O
Product: c1ccc(-c2nn3c(c2-c2cnc4ccnn4c2)CCC3)nc1
Yield: 26.2 %

Procedure:
To a microwave tube, add 6-bromo-pyrazolo[1,5-a]pyrimidine (0.175 g, 0.884 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (0.25 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol), 2M aqueous potassium carbonate (0.5 mL, 1.0 mmol) and dimethylsulfoxide (1.5 mL). Irradiate the reaction in a microwave reactor set at 110° C., 50 Watts, 10 min with external cooling. Dilute the reaction mixture with diethyl ether (250 mL) and extract the product into 0.1M aqueous hydrochloric acid (450 mL). Make the aqueous solution basic by adding 5M aqueous sodium hydroxide (25 mL) and extract with dichloromethane (300 mL). Filter the organic layer and concentrate under reduced pressure. Recrystallize the resulting solid from ethyl acetate, filter, rinse with ethyl acetate, and dry at 100° C. under vacuum to obtain 70 mg (26%) of the title compound as a tan solid. MS (electrospray, m/z) 302.9 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2cc(COc3cccc4cccnc34)ccc2c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
2-(bromomethyl) naphthalene (663 mg, 3 mmol) was added to a stirred mixture of 8-hydroxy quinoline (435 mg, 3 mmol), K2CO3 (621 mg, 4.5 mmol) in acetone (20 ml) at room temperature. The reaction mixture was stirred at rt over weekend and then partitioned between EtOAc and water. Water layer was extracted with EtOAc (2×100 ml). The combined organic phase was washed with water (2×100 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was washed with ether to give 650 mg of compound I-81. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6])[CH3:2].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>>[C:4]([C@@H:5]1[CH2:7][S:8][CH:10]([C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])[NH:6]1)([O:3][CH2:1][CH3:2])=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)[C@@H](N)CS
Product: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1

Procedure:
The procedure of M. Schubert (J. Biol. Chem., 114, 341 (1936)) was used to prepare 57 starting from L-cysteine ethyl ester and salicylaldehyde. Purification by silica gel chromatography afforded 57 as a thick oil. TLC (silica gel; 3:1 cyclohexane-EtOAc) showed a mixture of 2 isomers, Rf=0.4, 0.5. IR (film): 3300 (sharp), 3000, 1740, 1430 cm-1. NMR (CCl4): 1.28 (3H, t, J=7); 2.9-3.5 (2H, m); 3.8-4.4 (3H, m); 5.50, 5.80 (1H, 2x broad s); 6.5-7.3 (4H, m).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3.0 g, 0.01 mol) in phosphorous oxychloride (7.7 g, 0.05 mol) was heated and stirred at 100° C. for 1 hour. After the solution was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure, and the residue water was added to iced water. After neutralization by the addition of an aqueous sodium hydroxide solution, organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (ethyl acetate) gave the title compound (1.72 g, 54% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17].[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]2)([OH:18])[CH3:17])=[N:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: Brc1ccc(I)nc1
Agent: CC(C)[Mg]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-bromo-2-iodopyridine (18.5 g, 65.1 mmol) in THF (33 mL) at −5° C. was slowly added a solution of i-PrMgCl—LiCl (1.3 M in THF, 50.1 mL, 65.1 mmol) at such a rate that the internal temperature did not exceed −2° C. The reaction mixture was allowed to stir for 1.25 hours at 0° C., and methyl trans-4-acetylcyclohexanecarboxylate (6 g, 32.6 mmol) was added dropwise via syringe. The reaction mixture was stirred for an additional 1 hour at 0° C., then sodium borohydride (0.62 g, 16.3 mmol) was added. The reaction mixture was slowly allowed to warm to room temperature and stirred for 14 hours. The mixture was diluted by addition of saturated aqueous NH4Cl (200 mL) and DCM (250 mL). The layers were separated and the aqueous layer extracted with DCM (250 mL). The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo. The crude residue was absorbed on silica, gel and purified via silica gel column chromatography (EtOAc/Hexanes) to afford racemic methyl trans-4-[1-(5-bromopyridin-2-yl)-1-hydroxyethyl]cyclohexane carboxylate as a yellow oil. MS ESI calcd. for C15H21BrNO3 [M+H]+ 342 and 344. found 342 and 344. 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.4, 2.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 4.65 (s, 1H), 3.61 (s, 3H), 2.16 (m, 1H), 2.05-1.97 (m, 1H), 1.97-1.90 (m, 1H), 1.90-1.83 (m, 1H), 1.56 (m, 1H), 1.45 (s, 3H), 1.37 (m, 1H), 1.31-1.15 (m, 3H), 1.09 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN1C(=O)CCC1>[C:22]1([NH:21][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reaction time: 14 h
Yield: 89.4 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.58 mmol) and diisopropyl ethylamine (1.1 mL, 6.87 mmol) in NMP (10 mL) was added aniline (0.51 g, 5.49 mmol). The solution was stirred for 14 h to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 5 mL of water, dried (high vacuum, 14 h) to furnish N-phenyl-5-bromo-2-nitrobenzenamine (1.2 g), 90% yield. 1H NMR (500 MHz, CDCl3): δ 6.92 (dd, J=2 Hz, 1H), 7.35 (m, 5H), 7.51 (m, 1H) 8.11 (d, J=9.0 Hz, 1H), 9.55 (bs, 1H).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:24]([NH2:29])[CH:25]=[N:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:1]([CH2:2][CH2:3][CH3:4])=[N:29][C:24]=3[CH:25]=[N:26][C:27]=2[CH:28]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 105 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Trimethyl orthobutyrate (29.75 mL, 0.1859 mol) was added in three portions to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (54.6 g, 0.170 mol) in toluene (795 mL). Pyridine hydrochloride (1.96 g) was then added, and the reaction was heated at 105° C. and stirred for four hours. Additional trimethyl orthobutyrate (7 mL, 40 mmol) was then added, and the reaction was stirred for three hours. The reaction was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The oily residue was treated with chloroform, which was removed under reduced pressure to remove residual toluene, and then again diluted with chloroform (1.2 L). The resulting solution was washed with 5% aqueous sodium bicarbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to yield 60.3 g of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an oily brown solid, containing a small amount of toluene (0.93 equivalents).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[CH3:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25]>>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CNS(C)(=O)=O
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Product: CN(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)S(C)(=O)=O

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and N-methyl methanesulfonamide using a similar procedure to that described for Description 15.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+]>O1CCOCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:35])=[CH:17][C:18]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(SC)c3)c2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(SC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
The compound of example 15 (195 mg, 0.397 mmol) was dissolved in dioxane (2 ml), lithium hydroxide (1.99 ml of an aqueous 1 M solution, 1.99 mmol) was added, and the mixture was stirred at 60° C. for 1 h. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 180 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C@@H:12]([CH3:17])[CH2:13][C:14]([NH2:16])=[O:15])[CH2:9][CH3:10])=[C:4]([F:18])[C:3]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=[O:30].[K+].[K+]>CS(C)=O>[C:14]([CH2:13][C@@H:12]([NH:11][C@@H:8]([C:5]1[C:4]([F:18])=[C:3]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH2:28])=[O:30])=[CH:25][CH:26]=2)=[O:20])[C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH3:10])[CH3:17])(=[O:15])[NH2:16]
Reactant: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(C#N)cc2)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(C(N)=O)cc2)c1F
Reaction time: 2 h
Yield: 6 %

Procedure:
To (3S)-3-{[(1R)-1-{4-chloro-3-[(4-cyanophenyl)carbonyl]-2-fluorophenyl}propyl]amino}-butanamide (compound of Example 91) (0.016 g, 0.04 mmol) added DMSO (1 ml) treated with K2CO3 (0.027 g, 0.2 mmol) stirred ambient for 2 hours, further K2CO3 (0.027 g, 0.2 mmol) added left stirring ambient for 16 hours. Reaction purified by Prep HPLC to give 4-({3-[(1R)-1-{[(2S)-1-carbamoylpropan-2-yl]amino}propyl]-6-chloro-2-fluorophenyl}carbonyl)-benzamide (1 mg).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: Clc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(-c2ccccc2)cc1
Yield: 28 %

Procedure:
Ali et al., Tetrahedron, vol 48 (1992), pp. 8117-8126 discloses Suzuki-type cross-coupling reactions of arylboronic acids with pi-electron deficient heteroaryl chlorides (chloropyridines, chloropyrimidines, and chloropyrazines, chloroquinolines). These authors state, “It is widely accepted that palladium-catalyzed cross coupling reactions of arylboronic acids, and indeed of other organometallic species, proceed best with aryl or heteroaryl bromides or iodides, and either poorly, or more commonly, not at all with the corresponding chlorides.” These investigators confirmed early literature reports that reaction of phenylboronic acid with either chlorobenzene or 3-chloropyridine in the presence of tetrakis(triphenylphosphine) palladium failed to produce any coupled product. Using Pd(bis-1,4-(diphenylphosphino)butane)Cl2, however, they were able to get chlorobenzene to react to give 28% of biphenyl, and 3-chloropyridine was converted to 3-phenylpyridine in 71% yield. Among 2-chloropyridines, the reaction tolerated some (3-nitro, 5-chloro) but not other (3-OH, 3-CONH2) substituents.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[C:24]([Si:28]([CH3:38])([CH3:37])[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])[CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 3-[(5-bromo-2-methyl-benzoyl)amino]-2,4-dimethyl-benzoate (0.5 g, 1.32 mmol), tert-butyl-dimethyl-(3-piperidylmethoxy)silane (0.45 g, 1.99 mmol, see preparation 14) and Cs2CO3 (1.29 g, 3.98 mmol) in 1,4-dioxane (15 ml) is added Pd2(dba)3 (0.12 g, 0.132 mmol) followed by S-Phos (0.050 g, 0.132 mmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 110° C. After 6 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (silica gel) using 15% EtOAc in hexane as eluent to afford the title compound as a brown semi solid (0.6 g, 85%). Mass spectrum (m/z): 525.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[N:7]=1.Cl[Sn]Cl.CO.O>C1COCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1nc2cc([N+](=O)[O-])ccc2s1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nc2cc(N)ccc2s1

Procedure:
A mixture of nitro compound 456a (593 mg; 2.83 mmol); SnCl2 (4.02 g; 20.8 mmol; 7.35 eq) and NH4OAc (4.5 g) was suspended in THF:MeOH:H2O=1:1:1 (60 mL) and stirred at 70° C. for 2 h, cooled down, diluted with ethyl acetate and successively washed with saturated NaHCO3 and brine; dried (MgSO4) filtered and concentrated. The residue (443 mg; 2.43 mmol; 87%) showed consistent spectrum and suitable purity degree for synthetic purposes, therefore was submitted to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[S:6][C:7]([C:9]3[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:20][O:19][C:18]1[C:2]([O:1][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:3][C:4]2[CH:8]=[C:7]([C:9]3[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=3)[S:6][C:5]=2[CH:17]=1
Reactant: COc1cc2sc(C3=NNC(=O)CC3C)cc2cc1O
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2sc(C3=NNC(=O)CC3C)cc2cc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture of 4,5-dihydro-6-(5-hydroxy-6-methoxybenzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone (1.0 g), anhydrous potassium carbonate (1.0 g) and 1-(3-chloropropyl)piperidine hydrochloride (0.72 g) in dimethyl formamide (12 ml) was stirred at room temperature for 3 days. The mixture was then warmed to 65° C. and, after a further 2 hours, more anhydrous potassium carbonate (0.50 g) and 1-(3chloropropyl)piperidine hydrochloride (0.36 g) were added. After a further 2 hours the reaction mixture was cooled to room temperature and poured into water (60 ml). The product, which precipitated as a gum, was isolated by decantation and then crystallized from ethyl acetate to give 4,5-dihydro-6-(6-methoxy-5-[3-(piperidin-1-yl)propyloxy]-benzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone as a white solid (0.90 g), m.p. 198°-200° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4].CO.O1CCCC1.O.[OH-].[Li+]>O>[CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A solution of methyl 4-[5-(butylcarbamoyl)methyl-1-methylindol-3-ylmethyl]-3-methoxybenzoate (0.23 g) in a combination of methanol (2.5 ml), tetrahydrofuran (2.5 ml), and water (1.5 ml) was treated with lithium hydroxide monohydrate (0.14 g). The mixture was stirred for 18 hr and the organic solvents evaporated. The resultant aqueous solution was acidified with 10% (v/v) hydrochloric acid. The ivory precipitate which formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.21 g, 94%) as a pale pink powder: mp 92°-95°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([OH:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:13][CH2:11][CH3:12])=[O:5]
Reactant: CCO
Reactant: O=C(Cl)c1ccccc1F
Product: CCOC(=O)c1ccccc1F
Reaction time: 3 h

Procedure:
A mixture of 35 g of 2-fluoro-benzoyl chloride and 400 ml of ethanol was stirred for three hours and was allowed to stand overnight. The mixture was distilled to dryness at 50° C. and 30-40 mm Hg and the residue was taken up in methylene chloride The solution was washed with 5% aqueous sodium bicarbonate and then with water, dried and evaporated to dryness under reduced pressure. The product was rectified at 14 mm Hg to obtain 34 g of ethyl 2-fluoro-benzoate with a boiling point of 90°-91° C. at 14 mm Hg.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][NH:36]C(OC(C)(C)C)=O)=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[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]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][NH2:36])=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[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]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)CCCN(c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CCCC(=O)NN)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of tert-butyl 2-(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-6-yl)methylsulfonamido)butanoyl)hydrazinecarboxylate (40 mg, 0.065 mmol) in anhydrous CH2Cl2 (0.5 mL) under nitrogen was cooled to 0° C., and treated with trifluoroacetic acid (0.5 mL). The reaction was stirred at 25° C. for 1 hour. The mixture was concentrated by rotary evaporation, and the residue was diluted with ethyl acetate (50 mL), and washed with 5% aqueous NaHCO3 (2×10 mL) and brine (10 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The crude material was purified by SiO2 flash chromatography (Alltech Extract-Clean™ column, 5 g bed) eluting with a step gradient of 5% methanol/CH2Cl2 to 10% methanol/CH2Cl2 to afford the title compound as a white solid (16 mg, 0.031 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.64 (m, 1H), 0.80-0.90 (m, 1H), 0.92-1.08 (m, 2H), 1.59-1.75 (m, 2H), 2.02-2.17 (m, 2H), 2.34-2.42 (m, 1H), 3.15 (s, 3H), 3.55-3.77 (m, 2H), 4.12 (d, J=4.12 Hz, 2H), 7.08 (s, 1H), 7.18 (s, 1H), 7.28-7.43 (m, 3H), 7.85 (s, 1H), 8.02 (dd, J=9.00, 5.53 Hz, 2H), 8.93 (t, J=3.36 Hz, 1H), 12.41 (s, 1H); MS (ESI+) m/z 512 (M+H)+, 1023 (2M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:19][CH:18]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCOc1ccc(I)cc1

Procedure:
Quantities: anhydrous potassium carbonate (30 g, 0.22 mol), 1-bromooctane (11.7 g, 0.06 mol) and 4-iodophenol (11.0 g, 0.05 mol). The experimental procedure was as described in Example 119.