Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[N:6][CH:5]=1.Cl.[CH2:16]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:30][CH:29]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (216 mg, 1.0 mmol) and 4-benzyloxyaniline hydrochloride (280 mg, 1.2 mmol) in MeOH (10 mL) was added iPr2NEt (0.35 mL, 2.0 mmol). The resulting mixture was stirred at rt overnight, a red solid precipitated from the mixture, which was collected by filtration. MS (ES, Pos.): m/z 380 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.94 (s, 3H), 5.10 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.38-7.46 (m, 5H), 7.50 (d, J=8.8 Hz, 2H), 9.01 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 10.2 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][CH2:8][C:9]3([O:16]2)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:5][C:4]=1[NH2:19].CS([C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:25]2[N:24]=1)=O>>[CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][CH2:8][C:9]3([O:16]2)[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:5][C:4]=1[NH:19][C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:25]2[N:24]=1
Reactant: COc1cc2c(cc1N)CCC1(CCN(C)CC1)O2
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n1)CCC1(CCN(C)CC1)O2
Yield: 0.2 %

Procedure:
Following a procedure analogous to 251c, 7-methoxy-1′-methyl-3,4-dihydrospiro[chromene-2,4′-piperidin]-6-amine (0.15 g, 57 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (69 mg, 19 mmol) were converted to the title compound (23 mgs, 18%) isolated as a TFA salt. H-NMR (DMSO-d6) δ 9.49 (broad s, 1H), 8.92 (s, 1H), 7.94 (s, 1H), 7.65 (s, 2H), 7.69-7.66 (m, 3H), 6.98-6.94 (m, 2H), 6.52 (s, 1H), 3.80 (s, 3H), 3.39-3.31 (m, 2H), 3.23-3.13 (m, 2H), 3.06 (s, 3H), 2.87-2.81 (m, 7H), 2.55-2.51 (m, 2H), 2.00-1.91 (m, 2H), 1.84-1.76 (m, 32H); LC/MS (ESI+): 563.17 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:20]([N:22](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.CS(C)=O>[C:20]([CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:22]
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCC(CCO)CCc1cccnc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)CCCC(CCC#N)CCc1cccnc1
Reaction time: 0.5 h

Procedure:
A solution of 0.8 g (3.0 mmol) methyl 7-hydroxy-5-[2-(3-pyridyl)ethyl]-heptanoate in 3 ml methylene chloride is cooled to 0° and 0.52 ml (3.7 mmol) triethylamine is added followed by 0.26 ml (3.3 ml) methylsulfonyl chloride. The reaction mixture is stirred at 0° for 30 min and then 1.65 g (25 mmol) finely powdered potassium cyanide is added followed by 15 ml dimethyl sulfoxide. After stirring for 30 min the cold bath is removed and the mixture is stirred at room temperature for 18 h. The reaction mixture is poured on to saturated aqueous ammonium chloride solution and is then extracted with ethyl acetate (3×70 ml). Combined organic phase is washed with water (4×60 ml), brine (60 ml) and dried (MgSO4), filtered and evaporated to give an oil which is purified by flash chromatography to give both the desired methyl 7-cyano-5-[2-(3 -pyridyl)ethyl]-heptanoate and the mesylate of the starting alcohol. The mesylate is subjected to the cyanide displacement conditions described above to yield additional methyl 7-cyano-5-[2-(3-pyridyl)ethyl]-heptanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH:16]([F:18])[F:17])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]1.[Br:19][C:20]1[S:21][C:22]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[Br:19][C:20]1[S:21][C:22]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[C:23]([C:25](=[O:26])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH2:15][CH:16]([F:18])[F:17])[C:6]=2[N:7]2[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]2)[N:24]=1
Reactant: Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCCC(O)CC1
Yield: 69 %

Procedure:
Following the procedure for Intermediate 7 starting with 1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-ol and 2-bromo-5-(tert-butoxycarbonylamino)-thiazole-4-carboxylic acid afforded tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a colorless solid (265 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.14 (s, 1H), 8.02 (s, 1H), 6.18 (tt, J=55.9, 4.5 Hz, 1H), 4.38-4.27 (m, 2H), 3.33-3.12 (m, 5H), 2.20 (br s, 1H), 2.35-1.58 (m, 4H), 1.70-1.48 (m, 2H).
Reaction SMILES: [Na].[CH3:2][C:3]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4]2=[N:12][OH:13].[CH2:14](Br)[CH:15]=[CH2:16]>CO>[CH2:16]([O:13][N:12]=[C:4]1[CH2:5][CH:6]2[C:9]([CH3:10])([CH3:11])[C:3]1([CH3:2])[CH2:8][CH2:7]2)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CC12CCC(CC1=NO)C2(C)C
Agent: [Na]
Solvent: CO
Product: C=CCON=C1CC2CCC1(C)C2(C)C
Reaction time: 1 h

Procedure:
4.6 g (0.2 moles) of metallic sodium are dissolved in 200 ml of methanol, and 33.4 g (0.2 moles) of (±)-1,7,7-trimethyl-bicyclo(2.2.1)heptane-2-one-oxime are added to the solution. After one hour of boiling 24.0 g (0.2 moles) of allyl bromide are introduced, and the mixture is boiled for 3 hours. The suspension is cooled, the separated sodium bromide is filtered off, the filtrate is concentrated, and the concentrate is subjected to fractional distillation in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[CH:13])=[CH:7][CH:6]=2.[N:14]([Si](C)(C)C)=[N+:15]=[N-:16]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:16][NH:15][N:14]=1)=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2cnc(Cl)cc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc2cc(-c3cn[nH]n3)ccc2cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
3-chloro-6-ethynylisoquinoline (Preparation 50, 120 mg, 0.64 mmol) was dissolved in dry DMF (1 mL). Azidotrimethylsilane (1 mL, 7.5 mmol) was added and the reaction stirred at 120° C. for 2 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2% 7N NH3 in methanol in DCM followed by elution through an SCX-2 column using 50% methanol in chloroform followed by 50% 7N NH3 in methanol in chloroform to afford the title compound as a pale brown powder (90 mg, 61%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=[C:14]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:13]=2.[Cl:38][CH2:39][C:40](Cl)=O>ClCCl>[CH2:31]([O:30][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:40]([CH2:39][Cl:38])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Yield: 15.5 %

Procedure:
Triethylamine (24.0 mL, 172.58 mmol) was added to a solution of tert-butyl 2-[(3-amino-7-benzyloxyquinolin-4-yl)amino]ethylcarbamate (35.25 g, 86.29 mmol) in dichloromethane (400 mL), and the reaction was stirred at ambient temperature. Chloroacetyl chloride (6.87 mL, 86.29 mmol) was quickly added at ambient temperature, and the reaction was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (500 mL) and stirred for two days at ambient temperature. The mixture was concentrated under reduced pressure and the residue was recrystallized from dichloromethane to afford 6.23 g of tert-butyl 2-[7-benzyloxy-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate. The mother liquor was divided into two portions which were separately purified by normal phase prep HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 33-minute gradient from 0:100 to 5:95) and combined to provide an additional 24.21 g of product.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[C:10](O)=[O:11].CCN=C=NCCCN(C)C.C1C=CC2[N:53]([OH:54])N=NC=2C=1.NO>CN(C=O)C.C(OCC)(=O)C>[OH:54][NH:53][C:10]([C@@H:4]1[C@H:3]([N:2]([CH3:1])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C@@H:8]2[CH2:9][C@H:5]1[CH2:6][CH2:7]2)=[O:11]
Reactant: On1nnc2ccccc21
Reactant: CN(C1C2CCC(C2)C1C(=O)O)S(=O)(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO)S(=O)(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution of 3-{methyl-[4-(quinolin-2-ylmethoxy)-benzenesulfonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.268 mmol) in DMF (1 mL) were added EDCI (103 mg, 0.536 mmol), HOBT (72.5 mg, 0.536 mmol) and hydroxylamine (50% in water, 82 μL, 1.34 mmol) at room temperature. The mixture was stirred for 20 h, diluted with ethyl acetate (5 mL), and washed with water (3×3 mL) and brine (3 mL). The organic layer was concentrated and the residue was purified by RP-HPLC to give (1R,2S,3R,4S)-N-hydroxy-3-(methyl{[4-(quinolin-2-ylmethoxy)phenyl]sulfonyl}amino)bicyclo[2.2.1]heptane-2-carboxamide (50% yield). MS (ESI) [M+H] 482.2
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].N1C=CN=C1.[C:35]([Si:39](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][Si:39]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 615 mg (1.422 mmol) (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 126, Step B) in DMF (4741 μL) at 0° C. was added 1H-imidazole (97 mg, 1.422 mmol) followed by tert-butylchlorodiphenylsilane (473 μL, 1.849 mmol). The mixture was stirred at 0° C. for 15 min and then warmed to room temperature. The mixture was stirred at room temperature for 30 min and then quenched with sat. NH4Cl. The mixture was extracted with EtOAc and the organic layer was washed with water, 1 M LiCl, and sat. aq. NaCl solution. The mixture was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[CH:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[NH:5]1.I[CH2:33][C:34]#[N:35]>C(#N)C>[C:34]([CH2:33][N:5]1[CH:6]([C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[C:4]1=[O:3])#[N:35]
Reactant: N#CCI
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 11 mg, 0.29 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1, 40 mg, 96 μmol) in acetonitrile (3.0 mL). After 20 min, 2-iodoacetonitrile (7 μL, 0.1 mmol) is added. The mixture is stirred at room temperature over night and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 11 mg; ESI mass spectrum [M+H]+=437; Retention time HPLC: 0.63 min (X012_S01).
Reaction SMILES: [C:1]([C:8]([O:10]CC)=O)#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(=O)C>[OH:10][C:8]1[N:23]2[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[CH:25]=[C:24]2[N:26]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:1]=1
Reactant: COc1ccc(-c2cc(N)[nH]n2)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n2nc(-c3ccc(OC)cc3)cc2n1
Reaction time: 3 h

Procedure:
Diethyl acetylenedicarboxylate (883 μL, 5.6 mmol) was added to a solution of 3-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.1 g, 5.6 mmol) in acetic acid (5 mL). The very thick mixture was allowed to stand at room temperature with occasional stirring for 3 h. Ethyl acetate (5 mL) and hexanes (15 mL) were added and the precipitate was filtered, and dried under high vacuum. Yield: 1.26 g (76%); LCMS m/z 314.1 (M+H)+, ret. time=2.25 min.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[I-:18].[Na+]>C(#N)C>[I:18][CH2:2][O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(CCC(=O)OCc1ccccc1)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCC(=O)OCc1ccccc1)OCI

Procedure:
3-Benzyloxycarbonylpropionic acid chloromethyl ester (2 g, 1.38 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.6 g, 10.9 mmole) was added to the solution. After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave intermediate 3-benzyloxycarbonylpropionic acid iodomethyl ester in quantitative yield. This intermediate is bonded to an accessible function of a drug, such as a ring hydroxy or carboxy function using conventional alkylation/acylation conditions as described generally herein. Following deprotection of the terminal carboxy, a di/trifunctional linker bearing R2, such as 1,3-bis-O-(L-valyl)glycerol or iodomethyloxy-L-valyl is acylated/alkylated thereon or R2 amide bonded thereon by conventional techniques as described herein, such as with DCC coupling agent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].S(Cl)([Cl:18])(=O)=O.O>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([Cl:18])[C:6](=[O:13])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(=O)C(Cl)C(=O)OCC
Temperature: -9 °C
Yield: 215.2 %

Procedure:
Dissolve 3-oxo-pentanedioic acid diethyl ester (1122 g, 5.327 mol) in CH2Cl2 (3 L) and cool to −9° C. To the above solution, slowly add a solution of sulfuryl chloride (374 g, 2.69 mol) in CH2Cl2 (3 L) over 3 h. Upon completion, add a second charge of sulfuryl chloride (374 g, 2.69 mol) in CH2Cl2 (3 L) over 4 h. Stir the resulting cooled solution for one hour, then warm to room temperature and stir overnight. Cool the solution in an ice bath and slowly add water (8 L). Stir for 15 min, then separate the layers. Extract the aqueous layer with additional CH2Cl2. Combine the organic phases and wash with saturated NaHCO3 (3 L). Dry and concentrate the organic solution to obtain 1370 g (105%) of the title compound as a colorless oil. Use the material as-is in the next reaction without further purification. ES/MS m/z (35Cl) 235 [M−1]−.
Reaction SMILES: [CH3:1][C:2]([N+:20]([O-:22])=[O:21])([CH3:19])[CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl>[CH3:1][C:2]([N+:20]([O-:22])=[O:21])([CH3:19])[CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([OH:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(Cc1ccc(Oc2ccc(C=O)cc2)cc1)[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Oc2ccc(O)cc2)cc1)[N+](=O)[O-]
Reaction time: 1 h

Procedure:
4-(4-(2-Methyl-2-nitropropyl)phenoxy)benzaldehyde (6.00 g, 20 mmol) was dissolved in chloroform (500 mL). m-Chloroperoxy-benzoic acid (10.0 g, 58 mmol) was added in small portions at RT. After stirring for 1 hour, the mixture was concentrated in vacuo and MeOH (300 mL) added followed by the dropwise addition of conc. HCl (5 mL). This mixture was stirred for 3 hours at RT and then concentrated in vacuo. Chromatography over silica gel (MeOH/CHCl3) allowed for the isolation of 3.20 g (55%) of the desired product. MS(FD+): 287.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (1.27 g, 5.8 mmol) in MeCN (20 ml) was added 5-methyl-1H-pyrazol-3-ylamine (568 mg, 5.8 mmol) and Et3N (1.6 mL). The mixture was stirred at ambient temperature overnight. LC/MS showed the completion of the reaction. Evaporation of the solvent afforded yellow oil that was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (300 mg). m/z 278.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:29][CH:30]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 38.2 %

Procedure:
Into a solution of methyl 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g) in THF/methanol (10/5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 2 days. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid until the pH was adjusted to 2-3, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (425 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1.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.[Pd].[Cu](I)I>[C:20]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1OCc1csc(Br)n1
Reactant: C#CCCCC
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.7 %

Procedure:
To a solution of 2-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione (23.1 g, 68.1 mmol) in dry tetrahydrofuran (300 mL) were added 1-hexyne (11.2 g, 136 mmol), triethylamine (13.8 g, 136 mmol). The reaction mixture was degassed by blowing a flow of Argon through it, then palladium tetrakis(triphenylphosphine) (3.94 g, 3.41 mmol) and copper iodide (1.30 g, 6.81 mmol) were added. After stirring at room temperature for 21 h under argon, the mixture was concentrated in vacuo, diluted with water (800 mL) and ethyl acetate (900 mL), the organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded 2-{[2-(hex-1-yn-1-yl)-1,3-thiazol-4-yl]methoxy}-1H-isoindole-1,3(2H)-dione [13.6 g, yield 59%; HPLC/MS: m/z=341 (M+H); log P(HCOOH)=3.78].