Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:30]([C:34]1[CH:35]=[C:36]([NH:46][C:47](=O)[O:48]CC(Cl)(Cl)Cl)[N:37]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:38]=1)([CH3:33])([CH3:32])[CH3:31].CCOC(C)=O>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:47]([NH:46][C:36]3[N:37]([C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)[N:38]=[C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:35]=3)=[O:48])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
Place 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.718 mmol), diisopropylethylamine (0.125 mL, 0.718 mmol), and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid, 2,2,2-trichloro-ethyl ester (Preparation 38, 291 mg, 0.718 mmol) in DMSO (5 mL) and heat to 75° C. for 17 hours. Cool to room temperature and add EtOAc and water. Separate organic layer and wash with saturated aq. sodium chloride (2×20 mL). Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-70% EtOAc:hexane to yield 328 mg (85%) of 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester. MS(ES+): m/z=534.4 [M+H]).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:23][CH:24]([F:28])[C:25](O)=[O:26].[NH2:29][C:30]1[S:31][C:32]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:33][C:34]=1[C:35]([NH2:37])=[O:36]>[Cl-].[Na+].O.CN(C=O)C>[CH:38]1([C:32]2[S:31][C:30]([NH:29][C:25](=[O:26])[CH:24]([F:28])[F:23])=[C:34]([C:35]([NH2:37])=[O:36])[CH:33]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(O)C(F)F
Reactant: NC(=O)c1cc(C2CCCCC2)sc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(C2CCCCC2)sc1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of WSC hydrochloride (4.5 g), HOBt (3.2 g), and DMF (50 mL) were added difluoroacetic acid (2 mL) and 2-amino-5-cyclohexylthiophene-3-carboxamide (5.0 g), followed by stirring at room temperature for 3 days. To the reaction mixture was added 50% brine, followed by extraction with EtOAc. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate, water, and brine. To the organic layer were added MgSO4, and basic silica gel was added thereto, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 5-cyclohexyl-2-[(difluoroacetyl)amino]thiophene-3-carboxamide (7.0 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=O)=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Na].CN(C)C=O.O.C(Cl)(=O)C([Cl:30])=O>ClCCl.CCCCCCC>[C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:30])(=[O:19])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC#CCOc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 12 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of 4-(4-acetoxy-but-2-ynyloxy)-benzenesulfonic acid, sodium salt from Example 6 (360 g, 1.18 mol) in 2.1 L of dichloromethane in a 5-L 4-neck flask, was added N,N-dimethylformamide (14 g, 0.19 mol) and water (4.5 g, 0.25 mol). The mixture was cooled to 12° C. Oxalyl chloride (165 mL, 240 g, 1.89 mol) was added over 70 min while the temperature was maintained at 10–20° C. The mixture was slowly warmed to 23° C. over 1 h and stirred at this temperature for 1 h. The reaction was monitored for completion by HPLC (S.M. <3%). The mixture was quenched into 2 L of water in a 12-L flask at 30° C. After 5 min of stirring, the phases were separated and the organic phase was washed with water (1 L). The mixture was held at 0–5° C. overnight, resulting in clear phase separation. Dichloromethane was distilled off to a residual volume of about 700 mL. t-Butyl methyl ether (1.5 L) was added. Distillation was continued to a residual volume of 850 mL. The solution was cooled to 18° C. and seeded with crystals. After 35 min of stirring, product crystals formed. Heptane (650 mL) was added over 40 min while the temperature was maintained at 15–20° C. The mixture was heated to 35° C. to dissolve the product before it was cooled back to 20° C. More heptane (350 mL) was added over 10 min. The mixture was stirred at 15–20° C. for 40 min. The crystals were filtered in a funnel and washed with heptane (400 mL). The product was dried in vacuo at 23° C. to a constant weight (316 g, 89% yield). 1H NMR (300 MHz, CDCl3) δ 8.01 (m, 2H), 7.12 (m, 2H), 4.86 (t, J=1.8 Hz, 2H), 4.72 (t, J=1.8 Hz, 2H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3) ppm 170.5, 163.0, 137.2, 129.9, 116.0, 83.3, 80.2, 56.8, 52.3, 21.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:24]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])[CH2:36][CH2:35]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][N:37]2[CH2:38][CH2:39][N:34]([CH:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[CH2:35][CH2:36]2)=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCN(C2CCCc3ccccc32)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(C=Cc1cccnc1)NCCCCN1CCN(C2CCCc3ccccc32)CC1

Procedure:
Batch size: 2.7 g (18 mmol) 3-(3-pyridyl)-acrylic acid, 3.15 g (19 mmol) CDI and 5.0 g (17.4 mmol) 4-[4-(1,2,3,4-tetrahydro-naphthalin-1-yl)-piperazin-1-yl]-butylamine.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([CH:21]=[CH2:22])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(Br)cc2)C[C@@H]2CC[C@H]1N2C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1ccc([C@H]2C[C@@H]3CC[C@H]([C@H]2C(=O)OC)N3C)cc1

Procedure:
Scheme 5 provides exemplary synthetic route for 2β-carbomethoxy-3β-4′-(Z-2-iodoethenyl)phenyl)tropane (ZIET) and [123I] ZIET. The preparation of ZIET involved a five-step sequence of reactions. In this synthetic approach 2β-carbomethoxy-3β-(4′-bromophenyl)tropane was treated with vinyltributyltin to yield 2β-carbomethoxy -3β-(4′-ethenylphenyl)tropane. The vinyltropane derivative was converted to 2β-carbomethoxy-3β-(4′-formylphenyl)tropane followed by reaction with triphenyl-phosphoniumiodomethyne yllide to give ZIET.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]([O:24]CC)=[S:23].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]([OH:24])=[S:23]
Reactant: CCOC(=S)c1c(Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: OC(=S)c1c(Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 28.2 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-3-benzylthioindole-2-carboxylate (0.31 g) was dissolved in THF/methanol (1:1) and sodium hydroxide (2M, 2.0 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product (0.082 g, 28%); NMR d (CD3SOCD3) 4.04 (s, 2H), 5.72 (s, 2H), 6.83-7.62 (m, 12H); M/z (−) 442 (M+), 440, 428, 398, 396, 307, 305.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:16])[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][C:9]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=CC(=O)C=C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=CC(=O)C=C1
Yield: 70 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.36 g (3.33 mmol) of p-benzoquinone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.46 g of the desired product (yield 70%).
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21]CC2C=CC=CC=2)([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:29]>CO.C(Cl)Cl.C(OCC)C>[ClH:29].[NH2:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1
Reactant: NC(=O)C1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: NC(=O)C1(N)CNC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-benzhydryl-3-benzylaminoazetidine-3-carboxylic acid amide (I-2A-1d; 1.83 g, 4.80 mmol) in methanol/methylene chloride was added excess 1 M HCl in diethyl ether (3.5 ml). After stirring for 10 minutes, the solvent was removed, in vacuo, and the resultant hydrochloride salt dissolved in 10:1 methanol/water (55 ml). After the addition of 20% Pd(OH)2 on carbon (50% water; 0.37 g), the mixture was placed on a Parr®) shaker and then reduced (50 psi H2) at room temperature for 23 hours. The reaction was diluted with methanol (50 ml), filtered through a 0.45 μM disk, and the disk rinsed with methanol (2×100 ml). The combined methanolic solutions were concentrated, in vacuo, and then triturated from diethyl ether to afford I-3A-6a (262 mg, 85%) as a tan solid: +APcI MS (M+1) 115.8; 1H NMR (400 MHz, CD3OD) δ 4.58 (d, J=13.3 Hz, 2H), 4.47 (d, J=13.3 Hz, 2H).
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:21].[Na+].CO>C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH:2]([OH:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C[O-]
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(F)cc1

Procedure:
A mixture of ethyl 5-bromo-6-(4-fluorophenyl)-6-oxohexanoate (17.6 g), sodium formate (16.9 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml), and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, the residue was subjected to silica gel column chromatography, and ethyl 6-(4-fluorophenyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (13.8 g, 96%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Cl)C.C(O)C.[CH3:13][N:14]([CH3:16])[CH3:15]>>[CH3:13][N+:14]([CH2:7][CH2:6][CH2:5][C:4]([O-:3])=[O:9])([CH3:16])[CH3:15]
Reactant: CCOC(=O)CCCCl
Reactant: CN(C)C
Solvent: CCO
Product: C[N+](C)(C)CCCC(=O)[O-]
Temperature: 130 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
159 kg (0.92 kmol) of crude gamma-chlorobutyric acid ethyl ester (content 88 percent) and 107 kg (2.3 kmol) of ethanol were placed in a pressure agitator. Then 57 kg (0.96 kmol) of trimethylamine was added in 15 to 30 minutes. The temperature in this case rose to 30° to 50° C. Then heating to 130° C. was performed. The pressure in this case rose to 5 to 7 bars and then dropped back to about 4 bars. After a stable pressure was reached, it was cooled to 20° C. and the remaining triethylamine was removed. The reaction solution was adjusted to a pH greater than 11 with 138 kg of aqueous NaOH (30 percent). Then it was kept at 60° C. for 1 hour and the pH was optionally readjusted. Then it was cooled to 20° C. and the precipitated NaCl was filtered off. After removal by distillation of the excess triethylamine and solvent, the residue was diluted with water. This solution was adjusted to pH 8, filtered and desalted by electrodialysis. The resultant solution contained 32 percent of gamma-butyrobetaine corresponding to a yield of 80 percent, relative to the gamma-chlorobutyric acid ethyl ester. The content was 99.5 percent (HPLC determination of a dehydrated specimen).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1Br
Reaction time: 8 h

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (4.0 g, 18.60 mmol) in THF (93 mL) was cooled to 0° C. and LAH (1.41 g, 37.2 mmol) added by portion. After the reaction completed, aq. K/Na tartrate was added and the reaction stirred overnight. The aqueous layer was extracted with EtOAc and the organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo to give (2-bromo-3-methylphenyl)methanol as a clear oil that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:19][S@@](C(C)(C)C)=O)([CH2:12][C@@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[CH:9]([F:11])[F:10])[C:5]([F:26])=[CH:4][CH:3]=1.Cl>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[NH2:19][C@:8]([C:6]1[C:5]([F:26])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([CH:9]([F:11])[F:10])[CH2:12][C@H:13]([OH:18])[C:14]([F:15])([F:16])[F:17]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C[C@@H](O)C(F)(F)F)(c1nc(Br)ccc1F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N[C@](C[C@H](O)C(F)(F)F)(c1nc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (R)-N-((2S,4R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1,5,5,5-pentafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (28 mg, 0.059 mmol) in 1,4-dioxane (396 μl) was added hydrochloric acid, 4 M solution in dioxane (59.4 μl, 0.238 mmol) dropwise. The reaction mixture was stirred at RT for 1 h. The mixture was diluted with saturated Na2CO3 and extracted with EtOAc. The organic layer was washed with brine, and dried over sodium sulfate and concentrated in vacuo. The crude product was obtained as yellow oil. MS m/z=367, 369 M+, Calculated for C10H9BrF6N2O: 367.09.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[S:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][NH2:23])=[CH:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:16]4[CH:17]=[CH:18][S:14][CH:15]=4)[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(-c2ccsc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(-c4ccsc4)c3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-thiophen-3-yl-benzylamine (122 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-thiophen-3-yl-benzylamino)-2H-phthalazin-1-one: 38 mg (17.8%): m/z (M+H)=368. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.93 (d, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.64 (m, 3H), 7.52 (dd, 1H), 7.39 (m, 1H), 7.31 (m, 1H), 7.19 (dd, 1H), 6.87 (s, 1H), 4.47 (d, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:3]
Reactant: Clc1nc2ccccc2s1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1cccc(OCCCNc2nc3ccccc3s2)c1

Procedure:
3-[3-(Dimethylaminomethyl)phenoxy]propylamine (2.38 g) and 2-chlorobenzthiazole (1.94 g) were fused at 130° C. for 2 hours. The cooled residue was subjected to column chromatography on silica using chloroform followed by chloroform:methanol (25:1) as eluants to give the title compound as a yellow oil. This was converted to 2-[3-[3-(dimethylaminomethyl)phenoxy]propylamino]benzthiazole dihydrochloride (0.37 g), m.p. 154°-155° C. (recrystallised from ethanol/ether).
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([B:13]([OH:15])[OH:14])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+].[F:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1.C(OC(C)C)(=O)C>C1COCC1>[F:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([N:5]2[CH2:6][C:7]3[CH:12]=[C:11]([B:13]([OH:15])[OH:14])[CH:10]=[CH:9][C:8]=3[O:2][CH2:3][CH2:4]2)=[O:30])[CH2:25][CH2:24]1
Reactant: OB(O)c1ccc2c(c1)CNCCO2
Reactant: O=C(Cl)N1CCC(CF)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: O=C(N1CCC(CF)CC1)N1CCOc2ccc(B(O)O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (188 mg, 0.82 mmol) was taken into 50% aqueous THF (2 mL) followed by addition of solid sodium bicarbonate (360 mg, 4.3 mmol) then 4-(fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (218 mg, 1.21 mmol) in a minimum of THF. The mixture was stirred at room temperature over 1 h then partitioned with 0.5M aqueous hydrochloric acid and ethyl acetate. The organic solution was then brine washed, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was taken into isopropyl acetate and extracted once with 1M aqueous sodium hydroxide. The aqueous solution was then acidified to pH 2 using concentrated hydrochloric acid and extracted once with ethyl acetate then brine washed, dried over anhydrous sodium sulfate, filtered and concentrated to provide (4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (143 mg, 52% yield) as an amorphous residue. MS (EI) for C16H22BrFN2O4: 337 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]3([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>>[CH2:29]([N:14]([C:15]1([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N(Cc1ccccc1)C1(C(F)(F)F)CC1

Procedure:
In analogy to the procedure described in Example 16 b), 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16 a) was reacted with (chloromethyl)benzene (CAN 27987-13-9) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=482.4 [MH]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@@H:34]4[CH2:39][O:38][CH2:37][CH2:36][N:35]4C(OC(C)(C)C)=O)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@@H:34]4[CH2:39][O:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@@H]4COCCN4C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@@H]4COCCN4)c3)c3ccccc23)cc1
Yield: 59.2 %

Procedure:
A solution of the carbamate (9) (30 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 1 hr and was then evaporated in vacuo. the resulting residue was subjected to capture and release on SCX and then triturated from DCM (5.0 mL) and isohexane (5.0 mL) to afford the title compound (Example 11) as a brown solid (15 mg, 63%): m/z 634 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlapping m), 3.56-3.64 (4H, overlapping m), 3.82 (1H, m), 5.38 (2H, s), 6.34 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.42 (2H, m), 7.55-7.62 (3H, overlapping m), 7.91 (1H, m), 8.30 (1H, dd), 8.32 (1H, br s), 8.35 (1H, dd), 8.56 (1H, br s), 8.77 (1H, br s) 10.16 (1H, br s).
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)([C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:23])(OC)=O.C(C1CC(C2C=CC(Cl)=CC=2)(C#N)CCC1=O)(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[C:11]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:10][CH2:5][C:6](=[O:23])[CH2:7][CH2:8]1)#[N:12]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC)c2)CCC1=O
Agent: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Yield: 67 %

Procedure:
Following the same procedure described in Example 1, Part C, but substituting 29.0 gm. (0.0915 mole) of 2-carbomethoxy-4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 600 ml. acetic acid and 300 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, heating on the steam bath for 48 hours instead of 24 hours, and recrystallizing from a mixture of ethyl acetate and hexane instead of diethyl ether, there is obtained 16.83 gm. (67% yield) of the desired 4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone which has a melting point at 112.5° to 114.5° C.