Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.CN(C)C=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>O1CCCC1.CN(C)C1C=CN=CC=1>[OH:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:2]2[N:3]=[C:4]3[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]4[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=4)[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:41]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Reactant: OC1CCCNC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(N4CCCC(O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 68.4 %

Procedure:
The 2-hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (1.00 g, 3.19 mmol) obtained in (E) was dissolved in anhydrous tetrahydrofuran (15.0 ml) and anhydrous dimethylformamide (15.0 ml), added with 4-dimethylaminopyridine (585 mg, 4.79 mmol) and p-toluenesulfonyl chloride (730 mg, 3.83 mmol), and then the mixture was stirred at room temperature for 50 minutes. Subsequently, the reaction solution was added with 3-hydroxypiperidine (646 mg, 6.38 mmol) and stirred at room temperature for 16 hours, and then added with 3-hydroxypiperidine (968 mg, 9.57 mmol) and stirred at 60° C. for 1.5 hours. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5→100:10, v/v) to obtain the title compound (865 mg, 68%).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].N(OC(C)(C)C)=O.[Cl:25]CCCl>ClCCl.[Cu](Cl)Cl>[Cl:25][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCCCl
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 5-amino-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (200 mg, 0.861 mmol) and copper (II) chloride (116 mg, 0.861 mmol) in 1,2-dichloroethane (8 mL) was added tert-butyl nitrite (0.154 mL, 1.292 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was diluted with 30 mL of dichloromethane and was washed with 10 mL of 2M NH4OH solution, 10 mL of brine and dried over Na2SO4. Filtration and concentration yielded a crude product which was purified on silica gel column eluting with hexanes/EtOAc to afford ethyl 5-chloro-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:19]=[P:20](Cl)([Cl:22])[Cl:21]>C1(C)C=CC=CC=1>[P:20]([Cl:22])([Cl:21])([O:8][CH:6]1[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7]1)=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OP(=O)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99 %

Procedure:
A solution of 7.5 g (48 mmol) of (1S, 2R, 5S)-(+)-menthol (Aldrich) and 4.86 g (48 mmol) of triethylamine in 20 ml of toluene was dropped into 7.36 g (48 mmol) of POCl3 at 0° C. The entire solution was stirred for 23 hours at room temperature. The insoluble triethylamine hydrochloride was filtered and the solvent was evaporated. Yield 99%, 31P NMR δ 6.76 (CDCl3). (lit. T. Milobedzki, W. Janczak, Roczniki Chemji 11, 840 (1931)).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][C:6](=[N:9][OH:10])[CH2:7][CH3:8])[CH3:3].CO.C[O-].[Na+].O1C[CH2:19][CH2:18][CH2:17]1.C(Br)C=C>>[CH3:1][C:2](=[CH:4][CH2:5][C:6](=[N:9][O:10][CH2:19][CH:18]=[CH2:17])[CH2:7][CH3:8])[CH3:3]
Reactant: C1CCOC1
Reactant: CCC(CC=C(C)C)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C=CCBr
Product: C=CCON=C(CC)CC=C(C)C
Temperature: 0 °C

Procedure:
A reactor was charged with 1 mole of 2-methyl-5-hydroxyimino-2-heptene, 8 moles of methanol containing 1.2 moles of sodium methylate, and 10 moles of tetrahydrofuran (THF). The mixture was cooled to 0° C., and with stirring, 1.3 moles of allyl bromide was added dropwise over 5 minutes. The mixture was stirred at room temperature for one day. The reaction mixture was concentrated, and 40 parts of methylene chloride was added. The mixture was washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 2-methyl-5-allyloxyimino-2-heptene in a yield of 80 mole %. Identification of this compound was performed by using IR, NMR and mass spectra (the same techniques were used to identify compounds appearing hereinafter).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=2)[CH:13]=[N:12]1.Cl>C(O)C>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:2]3[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: Cn1ncc2cc(N)ccc21
Reactant: CSc1ccnc(Cl)n1
Agent: Cl
Solvent: CCO
Product: CSc1ccnc(Nc2ccc3c(cnn3C)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-4-(methylthio)pyrimidine (1.0 g, 6.2 mmol) and 1-methyl-1H-indazol-5-amine (1.0 g, 6.8 mmol) in 10 mL of ethanol was added 1 mL of concentrated hydrochloric acid at room temperature. The reaction mixture was heated at 80° C. for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was cooled to room temperature to form a solid. The resulting solid was collected by filtration and rinsed with cold ethanol to afford 1-methyl-N-(4-(methylthio)pyrimidin-2-yl)-1H-indazol-5-amine, intermediate 11 (0.7 g, 41%). The resulting solid was dissolved in 20 mL of dichloromethane and treated with m-chloroperbenzoic acid (mCPBA, 0.9 g, 5.2 mmol) at room temperature. After being stirred for 12 hours at room temperature, the reaction mixture was extracted with dichloromethane (×3) and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with heptane and then collected by filtration to afford the desired intermediate 12 as a white solid (0.6 g, 77%).
Reaction SMILES: C([N:6]1[CH2:33][CH2:32][C:9]2[N:10]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)(OCC)=O.[OH-].[K+]>C(O)C>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]3[N:10]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:9]4[CH2:32][CH2:33][NH:6][CH2:7][C:8]=4[C:16]=3[CH:15]=2)[CH:18]=1
Reactant: CCCCCCCCn1c2c(c3cc(-c4cccc(C)c4)ccc31)CN(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCn1c2c(c3cc(-c4cccc(C)c4)ccc31)CNCC2
Yield: 63.6 %

Procedure:
To the solution of 2-carbethoxy-8-m-tolyl-5-n-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (7) in ethanol was added the aqueous solution of potassium hydroxide. The mixture was refluxed for 16 h. The reaction mixture was concentrated to remove ethanol and extracted with DCM for three times (15 mL×3). The DCM layer was washed with brine, dried with Na2SO4, filtered and concentrated to give brow residue. This residue was purified by silica gel column chromatography to give yellow oil. Yield: 63.6%. 1H NMR (300 Hz, CDCl3) δ 7.62 (br, 1H), 7.48-7.41 (m, 3H), 7.36-7.32 (m, 2H), 7.15-7.12 (m, 1H), 4.12 (br, 2H), 3.99 (t, 2H, J=7.2 Hz), 3.31 (br, 2H), 2.91 (br, 1H), 2.79 (br, 2H), 2.45 (s, 3H), 1.77-1.73 (m, 2H), 1.32-1.28 (s, 10H), 0.90 (t, 3H, J=6.6 Hz). 13C NMR (75 Hz, CDCl3) δ 142.57, 138.05, 135.45, 133.83, 132.48, 128.46, 128.06, 126.89, 125.91, 124.37, 120.56, 116.20, 109.13, 108.09, 43.26, 43.01, 42.14, 31.75, 30.35, 29.28, 29.14, 27.05, 23.10, 22.56, 21.55, 14.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:39])([F:38])[F:37])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:38])([F:39])[F:37])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)C1
Solvent: CO
Product: O=C1OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)CC(O)=C1Cc1nc2ncc(Cl)cn2n1
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.131 g, 0.72 mmol) was added to a solution of example A(228) 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (0.230 g, 0.60 mmol) in MeOH (10 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (53 mg, 0.9 mmoL). After 15 hours the reaction mixture was quenched with concentrated HCl, and concentrated to a residual oil. Purification by flash column chromatography (EtOAc then 0%–5% MeOH in CH2Cl2) gave the product as a white solid (17 mg). 1H NMR (DMSO): δ 1.30–1.80 (brm, 8H), 2.08–2.18 (brm, 3H), 2.74 (s, 2H), 2.99(m, 2H); 3.15 (m, 2H), 3.47 (m, 3 H), 6.81 (m, 2H), 7.00(s, 1H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. For C26H26O4N4ClF3: C, 56.68; H, 4.75; N, 10.17. Found: C, 56.50; H, 4.69; N, 10.20.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][OH:16]>>[F:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([F:1])[C:3]([F:14])=[C:4]([O:16][CH3:15])[C:5]=1[C:11]#[N:12]
Reactant: CO
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Product: COc1c(F)c(F)c(C#N)c(F)c1C#N

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile was heated under reflux in 40 ml of methanol for 4 hours. The methanol was distilled off in vacuo to approximately one-fifth volume and ice water was then poured to the resultant mixture. The precipitated crystal was collected by filtration and was then washed with water and a small amount of cold methanol. After drying in vacuo, 1.6 g of the desired compound No. 20 was obtained.
Reaction SMILES: N1C=CC=CC=1.B.[N+:8]([C:11]1[CH:33]=[CH:32][C:14]([CH2:15][CH:16]2[C:27](=O)[NH:26][CH2:25][C:24](=O)[NH:23][CH2:22][C:21](=O)[NH:20][CH2:19][C:18](=O)[NH:17]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N+:8]([C:11]1[CH:33]=[CH:32][C:14]([CH2:15][C@H:16]2[CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C1CNC(=O)CNC(=O)C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)CN1
Agent: B
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(C[C@H]2CNCCNCCNCCN2)cc1
Temperature: 120 °C

Procedure:
Borane-pyridine (available from Aldrich) is added to a suspension of 2-(4-nitrobenzyl)-3,6,9,12-tetraoxo-1,4,7,10-tetraazacyclododecane in pyridine. The mixture is heated under reflux at 120° C. for 14 hours. The solvent is removed under reduced pressure. The residue is taken up in methanol and heated under reflux for 2 hours. The solvent is removed under reduced pressure. The residue is dissolved in methanol and re-evaporated. The solid residue is purified by chromatography on reverse phase Baker G18 silica gel available from J. T. Baker, Inc., Phillipsburg, N.J. Conversion of this product to nitro-benzyl-DOTA is accomplished via the procedure discussed in Rennet al., Bioconj. Chem., 3:563-569, 1992 or as set forth is subpart A above.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([Cl:18])=[O:14]
Reactant: O=C(O)/C=C1\CCc2c(Cl)cccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C1\CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4-chloro-1-indanylidene) acetic acid (5.5 g, 0.03 mol) in a mixture of dimethylformamide: dichloromethane (5 drops: 50 mL) was treated with oxalyl chloride (6.6 g, 0.05 mol) and allowed to stir at room temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.
Reaction SMILES: [CH2:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-dodecylsuccinic anhydride (42.17 g, 147.4 mmol), 3-(3,5-di-t-butyl-4hydroxyphenyl)propanoic acid hydrazide (43.31 g, 147.4 mmol) and 70 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (160° C.) melt for about 10 minutes. The resulting yellow liquid was then cooled under vacuum to about 120° C. The vacuum was released and the melt was quickly poured into a container. Upon cooling, the liquid became a clear yellow glass. The product was recrystallized from acetone/water at ice bath temperatures to afford, after drying, a nearly quantitative recovery of the product as a white powder having a melting range of 55°-60° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(Cl)ccc1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 62.6 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,5-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.95 g, 6.06 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.5 g, 8.18 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.35 g, 70%) was obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][C@H:8](O)[CH2:9][CH2:10][C@@H:11]1[C@@H:20]2[C:15](=[CH:16][C@@H:17]([OH:22])[CH2:18][C@@H:19]2[OH:21])[CH:14]=[CH:13][C@@H:12]1[CH3:23])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O1CCCC1>[OH:22][C@H:17]1[CH2:18][C@H:19]([OH:21])[C@H:20]2[C:15]([CH:14]=[CH:13][C@H:12]([CH3:23])[C@@H:11]2[CH2:10][CH2:9][C@H:8]2[O:5][C:4](=[O:6])[CH2:3][C@H:2]([OH:1])[CH2:7]2)=[CH:16]1
Reactant: C[C@H]1C=CC2=C[C@@H](O)C[C@H](O)[C@@H]2[C@H]1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1

Procedure:
The whole of the crude (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6,8-dihydroxy-2-methyl-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoic acid, prepared as described in Step 2, above, was mixed with 1000 ml of tetrahydrofuran. 38 ml (0.27 mol) of triethylamine were then added to the mixture, followed by 38 ml (0.25 mol) of diethyl cyanophosphonate, whilst ice-cooling and stirring. The resulting mixture was then stirred at room temperature for 1.5 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure and the residue was triturated with a mixture of diethyl ether and ethanol to stimulate crystallization. The resulting crystals were collected by filtration to provide 47.7 g of the title compound. This was then recrystallized from a mixture of ethyl acetate and ethanol to produce colorless plates melting at between 161° and 163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([O:17][CH2:18][CH2:19][NH2:20])[CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([O:17][CH2:18][CH2:19][NH:20][C:4](=[O:5])[C:3]1[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:16]
Reactant: CCOCCN
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: CCOCCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Yield: 66.2 %

Procedure:
The compound of Example b (4.94 g, 20 mmol), 2-ethoxyethyl amine (3.92 g, 44 mmol), and toluene (35 mL) were combined according to General Method E1. The crude product was recrystallized from aq ethanol to afford 3.97 g of N-(2-ethoxyethyl)-2-chloro-6-(trimethylsilyl)benzamide as white solid, a 66% yield. m.p. 71-73° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:38]2[CH:39]=[C:40]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[CH:49][N:48]=3)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:34])([CH3:35])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCOCC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Yield: 53 %

Procedure:
Following Example 148b, starting with 400 mg of (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b and 284 mg 5-bromo-1-methyl-3-(5-morpholinopyridin-2-ylamino)pyridin-2(1H)-one 255c, 277 mg of 256a was obtained as a yellow solid (53%). MS: [M+H]+ 672
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[CH3:20])=[O:18])=[CH:13][C:12]=23)=[CH:4][CH:3]=1.C(OC([NH:36][CH2:37][C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:36][CH2:37][C:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=4)[CH3:20])=[O:18])=[CH:13][C:12]=23)=[CH:4][CH:3]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN(C(=O)c1ccn2ncc(-c3ccc(N)cc3)c2c1)c1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccn2ncc(-c3ccc(NC(=O)CN)cc3)c2c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 42 (1.0 equiv.) in CH2Cl2 (˜0.1 M) was treated with 2-((tert-butoxycarbonyl)amino)acetic acid (1.2 equiv.), followed by HATU (1.1 equiv(2.5 equiv.). The resulting mixture was allowed to stir at rt for two hours, and then was filtered and treated with one volume of TFA. The resulting solution was allowed to stir at rt for 30 minutes, and the solvents were removed under reduced pressure. The residue was purified by mass-triggered HPLC to provide the desired product. ESI-MS (m/z): [M+H]+ 425.1, RT 1.1033 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][S:7]1(=[O:12])=[O:11].[CH2:19]([Li])CCC.IC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([CH3:19])[S:7]1(=[O:12])=[O:11]
Reactant: [Li]CCCC
Reactant: COc1ccc(CN2CCCS2(=O)=O)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2CCC(C)S2(=O)=O)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of 2-(2,4-dimethoxybenzyl)isothiazolidine-1,1-dioxide (0.600 g, 2.2 mmol) in anhydrous tetrahydrofuran (29 mL) was slowly added n-butyl lithium (1.725 mL of a 2.5 N solution in hexanes, 4.3 mmol). The reaction mixture was stirred for 1 hr at −78° C., iodomethane (0.688 mL, 11.1 mmol) was added, and the resulting mixture stirred for 2.5 hrs at −78° C. and 30 mins at room temperature. The mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (20-60% ethyl acetate/hexanes) to give the product as a clear oil (0.3 g). 1H NMR (CDCl3, 300 MHz) δ 7.25-7.22 (d, 1H, J=8.1 Hz), 6.48-6.43 (m, 2H), 4.27-4.13 (q, 2H, J=14.1 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 3.25-3.02 (m, 3H), 2.43-2.32 (m, 1H), 1.95-1.83 (m, 1H), 1.42-1.40 (d, 3H, J=6.6 Hz).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:27])[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:13]=[CH:12]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>ClCCl>[CH2:20]([S:19][C:18]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:15]2=[O:27])=[CH:10][C:9]=1[O:8][C@@H:5]1[CH2:4][CH2:3][C@H:2]([NH:1][C:44](=[O:46])[CH3:45])[CH2:7][CH2:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](N)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
45 mg (0.073 mmol) of 6-(4-amino-cis-cyclohexyloxy)-7-benzylsulfanyl-2-(4-methoxy-benzyl)-2H-iso-quinolin-1-one (127) were dissolved in 5 ml of dichloromethane and 14.8 mg (0.146 mmol) of triethylamine were added. At 0° C., 6.9 mg (0.088 mmol) of acetylchloride were added and the solution was stirred at room temperature. After 2 h, dichloromethane was added and the solution was washed with 2 N HCl and saturated sodium bicarbonate solution. After drying with magnesium sulfate and evaporation of the solvent, the title compound was isolated as crude product, which was used without further purification. Rt=1.53 min (Method C). Detected mass: 543.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[Cl:1][C:2]1[C:7]([NH:8][C:13]2[C:14](=[O:19])[C:15](=[O:16])[C:12]=2[O:11][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccnc1Cl
Solvent: CCO
Product: CCOc1c(Nc2cccnc2Cl)c(=O)c1=O

Procedure:
A solution of 2-chloro-3-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound.