Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C(O[C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN[C@H]1CC[C@H](CO)CC1
Temperature: 50.54999923706055 °C

Procedure:
Vitride solution (65%, 767 ml, 2.465 mol) was added dropwise over 1 h to a solution of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (commercially available, 100 g, 0.4109 mol) in toluene (1 l). After the addition was complete the reaction mixture was heated to reflux for 100-1.10° C. The reaction mixture was quenched with aq. Sodium sulphate solution (800 ml) at temperatures below 10° C. The reaction mixture was filtered through celite and the filter cake washed with DCM (500 ml) followed by water (100 ml). The organics layer was separated and the aqueous layer extracted twice with DCM (600 ml then 400 ml). The combined organics layers were dried over sodium sulphate and concentrated in vacuo to give the title compound (62 g).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[CH:11]=CC=C[CH:7]=1.C1(C=O)CC1>>[CH3:35][N:2]([CH3:1])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[CH:6]1[CH2:7][CH2:11]1
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Agent: O=CC1CC1
Product: CN(C)C(=O)OC(c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C)C1CC1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 97 but using cyclopropanecarboxaldehyde in place of benzaldehyde. Colourless gum (14 mg, 68%);
Reaction SMILES: C([N:4]([CH2:19][CH:20]=[CH2:21])[C:5]1[N:10]=[C:9]([N:11](CC=C)[CH2:12][CH:13]=[CH2:14])[N:8]=[C:7](Cl)[N:6]=1)C=C.[NH:22]([CH:40]1[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]1.[OH-].[Na+].C1(C)C(C)=C[CH:55]=[CH:56][CH:57]=1>O>[CH3:46][C:44]1([CH3:47])[CH2:45][CH:40]([N:22]([C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:10]=[C:5]([NH:4][CH2:57][CH:56]=[CH2:55])[N:6]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]([C:7]2[N:6]=[C:5]([NH:4][CH2:19][CH:20]=[CH2:21])[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=2)[CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:38])([CH3:39])[CH2:31]2)[CH2:41][C:42]([CH3:49])([CH3:48])[NH:43]1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CCN(CC=C)c1nc(Cl)nc(N(CC=C)CC=C)n1
Reactant: Cc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNc1nc(NCC=C)nc(N(CCCCCCN(c2nc(NCC=C)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1

Procedure:
A mixture of 2,4-bis(diallylamino)-6-chloro-1,3,5-triazine (14.2 grams; 0.046 mole), 4,4'-(hexamethylenediimino)bis(2,2,6,6-tetramethylpiperidine) (9.2 grams; 0.023 mole), powdered sodium hydroxide (1.84 grams; 0.046 mole), and xylene (50 mls) is heated at reflux for 36 hours using a water separator to remove byproduct water. The reaction mixture is then filtered hot and the filtrate is evaporated to obtain a light yellow oil which solidifies on standing. Recrystallization of the solid from hexane gives white needles which on recovery and drying weigh 9.3 grams, mp 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])C=O)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:41]([CH:46]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:43][CH2:44][CH3:45])=[O:42].[C:66]1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH:66]=[CH:46][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C=O)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: CCOC(=O)C=CC(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6 %

Procedure:
A solution of ((1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-[1-methyl-2-oxoethyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 141, 94 mg, 0.163 mmol) and carbethoxymethylene triphenylphosphorane (68 mg, 0.195 mmol) in anhydrous toluene (5 ml) was refluxed under nitrogen for 3 hours and then stirred at room temperature for 18 h before concentrating in vacuo. The residue was treated with sulfuric acid (10%) and extracted with two aliquots of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was taken up in acetonitrile (1 ml), filtered, and purified by preparative HPLC on a Dynamex®, 5 mm×21.6 mm column, eluting with acetonitrile:water (60:40). The pure fractions were concentrated in vacuo to give the title product (7 mg, 6%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1ccc(CO)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(COc2nc(N)nc(-c3ccccn3)c2C#N)nc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=O)=[C:4]([N+:18]([O-])=O)[CH:3]=1.S(Cl)(Cl)=O.CNC.C[N:29](C)[C:30](=[O:48])[C:31]1[CH:36]=CC=C[C:32]=1SC1C=CC(Br)=CC=1[N+]([O-])=O.[H][H]>[C].[Pd]>[NH2:18][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][C:31]([CH3:36])([CH3:32])[C:30]([NH2:29])=[O:48]
Reactant: [H][H]
Reactant: O=C(O)c1ccccc1Sc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C(=O)c1ccccc1Sc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CNC
Solvent: O=S(Cl)Cl
Product: CC(C)(Cc1ccccc1Sc1ccc(Br)cc1N)C(N)=O

Procedure:
In order to achieve the above objects, a method for preparing a radiotracer precursor SnADAM of the present invention includes following steps. First, 2-[(4-bromo-2-nitrophenyl)thio]benzoic acid is activated by thionyl chloride (SOCl2) and reacted with dimethylamine to carry out an amidation reaction for production of N,N-Dimethyl-2-[(4-bromo-2-nitrophenyl)-thio]-benzamide. Then catalyze and reduce N,N-Dimethyl-2-[(4-bromo-2-nitrophenyl)thio]-benzamide by using palladium carbon catalyst and hydrogen gas to produce [2-((2-amino-4-bromo-phenyl)thio)benzyl]dimethylacetamide. Next, reduce [2-((2-amino-4-bromo-phenyl)thio)benzyl]dimethylacetamide by borane to produce N,N-dimethyl-2[(4-bromo-2-nitrophenyl)thio]-dimethylamine. Add bis(tri-n-butyltin) into N,N-dimethyl-2-[(4-bromo-2-nitrophenyl)thio]-dimethylamine for carrying out substitution reaction and using tris(dibenzylideneacetone)-dipalladium(0) as a catalyst so as to produce [2-((2-Amino-4-tri-n-butyltinphenyl)-thio)benzyl]-dimethylamine which is a radiotracer precursor. Thus SnADAM, the precursor of the radiotracer for imaging of serotonin transporter, can be produced at a fast rate and in a large quantity according to the steps mentioned above.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9].[N-:10]=[N+:11]=[N-:12].[Na+].O>CN(C)C=O>[N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9])=[N+:11]=[N-:12]
Reactant: BrCc1ccccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
After a mixture of 30 g (120 mmol) of 1-bromomethyl-2-bromobenzene and 15.6 g (240 mmol) of sodium azide in 300 ml of dimethylformamide was stirred at 25° C. for 20 hours it was poured into 500 ml of water and extracted with ethyl acetate. The extracts were washed with water and brine, dried (Na2SO4) and concentrated to give 24.9 g (98%) of the product as an oil.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:10].[C:14]([OH:17])(=[O:16])[CH3:15].[C:18]([OH:21])(=[O:20])[CH3:19].[CH2:22]([C:42]1[C:47]([OH:48])=[C:46]([CH3:49])[C:45]([CH3:50])=[C:44]([OH:51])[C:43]=1[CH3:52])/[CH:23]=[C:24](/[CH2:26][CH2:27][CH2:28][C@@H:29]([CH2:31][CH2:32][CH2:33][C@@H:34]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH3:35])[CH3:30])\[CH3:25]>C(O)(=O)C>[C:14]([OH:17])(=[O:16])[CH3:15].[C:18]([OH:21])(=[O:20])[CH3:19].[CH3:49][C:46]1[C:47]([OH:48])=[C:42]([CH2:22][CH2:23][C:24]([CH3:25])([NH:8][C:1](=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:27][CH2:28][CH:29]([CH3:30])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:40])[CH3:41])[C:43]([CH3:52])=[C:44]([OH:51])[C:45]=1[CH3:50]
Reactant: N#Cc1ccccc1
Reactant: C/C(=C\Cc1c(C)c(O)c(C)c(C)c1O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1c(C)c(O)c(CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)NC(=O)c2ccccc2)c(C)c1O
Temperature: 0 °C
Reaction time: 10 h
Yield: 84.3 %

Procedure:
To a mixture of benzonitrile (10 g, 96.97 mmol), concentrated sulfuric acid (10 g) and glacial acetic acid (40 mL) was added, with stirring at 0° C., the diacetate (32, 10 g, 19.43 mmol). The solution was stored for 10 h at room temperature, then poured onto ice (150 mL) and extracted with ether (3×100 mL). The ether extracts were washed neutral with water (3×100 mL), and saturated sodium bicarbonate solution, dried (Na2SO4) and evaporated in vacuo. The crude product (21 g) was chromatographed on silica gel eluting with petroleum ether:ether (9:1). The unchanged benzonitrile was first removed. Elution with ether then afforded 11 g (88%) of product which was crystallized from petroleum ether to give analytical sample (33) m.p. 90-92° C. (lit.1 94-95° C.).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23]([N:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:24])([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc(C2CNCc3ccccc32)cc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C(c2ccccc2)C1

Procedure:
Prepared in analogy to example 1.1 from 4-phenyl-1,2,3,4-tetrahydro-isoquinoline (CA [42923-77-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl[Si](C)(C)C.[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30]C([O-])=O.[K+].C1CCN2C(=NCCC2)CC1>C1COCC1.C(#N)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](=[O:6])[CH2:30][C:29]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(I)ccc1F
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a stirred solution of 5.32 g of 2-fluoro-5-iodobenzoic acid from Preparation No. 7 in 20 mL of THF, under argon, is added 3.9 g of carbonyldiimidazole. In a separate flask, 2.8 mL of chlorotrimethylsilane is added to a mixture of 3.74 g of potassium ethyl malonate in 20 mL of acetonitrile. The mixture is stirred under argon for 18 h, then cooled to 0° C. for the dropwise addition of 6.6 mL of DBU. The mixture is stirred for 3 h at 0° C., then the solution of acyl imidazolide prepared above is added via cannula. After 2 hours, the mixture is partitioned between ether and excess dilute HCl, and the organic phase is washed with dilute HCl and brine and dried (MgSO4). Removal of the solvent under reduced pressure left a colorless oil, which is flash chromatographed on silica using 10% ethyl acetate in hexane to provide 5.07 g of the title compound as dense pinkish prisms.
Reaction SMILES: C([N:4]([CH2:8]C)C(C)C)(C)C.Cl.CN[O:13][CH3:14].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([O:43][C@H:44]([CH3:60])[C@H:45]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:46][O:47][CH2:48][C:49]([OH:51])=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:56]([O:55][C:53](=[O:54])[NH:52][C@H:45]([CH2:46][O:47][CH2:48][C:49](=[O:51])[NH:4][CH2:8][O:13][CH3:14])[C@H:44]([O:43][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH3:60])([CH3:59])([CH3:58])[CH3:57]
Reactant: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNOC
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCNC(=O)COC[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reaction time: 16 h

Procedure:
N,N-diisopropylethylamine (41 mL), N,O-dimethylhydroxyamine hydrochloride (17.4 g), EDCI (34.3 g), HOBt (24.1 g) were added in sequence to a DMF (400 mL) solution of ((2R,3R)-3-benzyloxy-2-t-butoxycarbonylaminobutoxy)acetic acid (42.1 g), and stirring was continued for 16 hours at room temperature. The solvent was removed under a vacuum, and ethyl acetate and water were added, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum. After passing the residue through a silica pad (silica gel 500 cc), the solvent was removed under a vacuum, and the title compound (46.0 g) was obtained. The physical property values are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:22]1([S:28]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH2:5][CH:6]([NH:12][S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH2:7]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(NC1Cc2cc(Br)ccc2N(S(=O)(=O)c2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of compound 87A (98 mg, 0.299 mmol) in pyridine (3 mL) was added benzenesulfonyl chloride (0.042 mL, 0.33 mmol). The mixture was stirred at RT overnight, then concentrated. The residue was chromatographed (10 g silica gel) eluting with EtOAc (0-60%) in hexane to give the title compound (140 mg, 93%) as a white foam. HPLC: 99% at 7.06 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 529 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Br:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)CC)C>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Br)ncc2[N+](=O)[O-])C1
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 3-(aminomethyl)-1-boc-piperidine (409 mg, 1.91 mmol) in acetonitrile (2.5 mL) was added dropwise to a solution of 2-bromo-4-chloro-5-nitropyridine (431 mg, 1.82 mmol) and triethylamine (0.28 mL, 2.0 mmol) in acetonitrile (10 mL). The solution was stirred for 1 hr then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (×3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate as a yellow-brown solid (718 mg, 95%) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:20][N:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Br[C:33]1[S:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=1.C(N(CC)CC)C>ClCCCl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:39][CH:38]([C:35]1[N:34]=[C:33]([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][O:24][C:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([CH3:8])(=[O:10])=[O:11])=[CH:13][CH:14]=4)=[N:19][CH:20]=3)[CH2:27][CH2:28]2)[S:37][N:36]=1)[CH3:40]
Reactant: CC(C)c1nsc(Br)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)c1nsc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Yield: 37.1 %

Procedure:
A mixture of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine trifluoroacetate (107 mg, 0.23 mmol), 5-bromo-3-(1-methylethyl)-1,2,4-thiadiazole (48 mg, 0.23 mmol), triethylamine (0.096 mL, 0.69 mol) and 1,2-dichloroethane (3 mL) was stirred and heated at reflux for 2 h, and the mixture was concentrated. The crude product was purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (30:70 to 70:30) with 0.05% TFA as a modifier to give 25 mg (19%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.49 (d, 1H, J=2.6 Hz), 8.13-8.06 (m, 2H), 8.06-7.99 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 7.39 (dd, 1H, Ja=8.8 Hz, Jb=2.6 Hz), 4.06-3.94 (m, 4H), 3.27-3.17 (m, 2H), 3.12-2.99 (m, 4H), 2.23-2.08 (m, 1H), 2.05-1.95 (m, 2H), 1.65-1.50 (m, 2H), 1.31 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 473 (M+H).
Reaction SMILES: [Na+].[I-].Br[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.N1([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)CCCC1.[OH2:24]>CCO>[O:24]=[C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: O
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(CC2CCCCC2=O)cc1

Procedure:
NaI (1 g) was added to a solution of 4-Bromomethyl benzonitrile (12.9 g, 0.066 mol) and 1-(pyrrolidino-1-cyclohexene (10 g, 0.066 mol) in EtOH (150 ml). After 1 night at RT, the reaction mixture was poured into water (500 ml) and extracted twice with EtOAc. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated to yield 4-[(2-oxocyclohexyl)methyl]-benzonitrile (7.06 g) as a yellow oil. 1H NMR (CDCl3): 7.60 (2H, d), 7.30 (2H, d), 3.25 (1H, dd), 2.7-2.2 (4H, m), 2.2-1.2 (6H, m).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[O:15])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(NCc1cccc(F)c1)NNC(=O)c1ccc2c(c1)CCO2
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(CNc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 11.1 %

Procedure:
A solution of 2-(2,3-dihydro-1-benzofuran-5-ylcarbonyl)-N-(3-fluorobenzyl)hydrazinecarboxamide (0.50 g, 2.81 mmol), polystyrene resin-immobilized triphenylphosphine (2.15 mmol/g, 0.76 g, 1.64 mmol), triethylamine (0.17 mL, 1.22 mmol) and carbon tetrachloride (0.12 mL, 1.22 mmol) in tetrahydrofuran (5 mL) was stirred at 80° C. for 4 hr. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (97 mg, yield 51%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH3:13]>>[N:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([NH2:13])=[O:2])=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)CCc1ccncc1
Product: NC(=O)CCc1ccncc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The crude ester was dissolved in 250 mL of 7.1M methanolic ammonia solution and was stirred at room temperature for 65 hours. After the solvent and excess ammonia were removed by distillation under reduced pressure, the residue was dissolved in 150 mL of 1N HCl and extracted with dichloromethane to remove residual triphenylphosphine oxide. The aqueous phase was basified with 40 mL of 4N NaOH and then was extracted with ethyl acetate (5×300 mL). The dried (Na2SO4) extracts weer evaporated to furnish 6 g of the amide. The aqueous layer was concentrated to dryness and triturated with tetrahydrofuran (4×100 mL) and evaporation of the tetrahydrofuran extracts yielded an additional 5 g of amide. The combined crude products were dried, triturated with ether and the solids were filtered to yield 10.7 g of 4-pyridinepropanamide, mp 164°-166° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[CH:3]1.[CH2:9](O)[CH2:10][CH2:11][OH:12].O>C1(C)C=CC=CC=1.C(Cl)Cl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[O:8]1[CH2:9][CH2:10][CH2:11][O:12][CH:7]1[C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1
Reactant: OCCCO
Reactant: Cn1cncc1C=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cncc1C1OCCCO1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 1-methyl-1H-imidazole-5-carbaldehyde (2.9 g, 26.3 mmol) in toluene (20 mL) was added propane-1,3-diol (4.01 g, 52.7 mmol) and CSA (0.306 g, 1.317 mmol) and the reaction mixture was heated to reflux with azeotropic removal of the evolved water for 24 hours. The reaction mixture was cooled to RT, diluted with DCM and washed with NaHCO3 solution. It was then dried over Na2SO4, filtered and concentrated. Purification by column chromatography (80% EtOAc in Hexane to EtOAc) afforded 38 (2.53 g, 57% yield) as a yellow oil which solidified on standing to a yellow solid. MS (m/z): 169.2 (M+H).