Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
At 0° C., NaH (1.88 g, 46.2 mmol) was added to a solution of 5-fluoro-1H-indole (5.2 g, 38.5 mmol) in 40 mL DMF. After 10 min at 0° C. tert-butyldimethylsilyl chloride (6.96 g, 46.2 mmol) was added and the mixture allowed to stir at 0° C. for an additional 1 h. The mixture was warmed to room temperature and stirred overnight, then diluted by the addition of water and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography to give the title compound (6.5 g, 67.7%)
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[NH:32][CH:31]=[CH:30]2>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:30]2[C:29]3[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=[C:27]([F:26])[CH:28]=3)[NH:32][CH:31]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
128 mg (0.58 mmol) of indium(III) chloride and 0.07 ml (0.87 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 167A and 149 mg (0.58 mmol) of the compound from Example 87A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 130 mg (65% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BrH:10].BrBr>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cccnc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cccnc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-acetylpyridine (5.00 g, 41.3 mmol) in acetic acid (100 ml) was added 47% hydrobromic acid (7.10 ml, 41.3 mmol), and a solution of bromine (2.12 ml, 41.3 mmol) in acetic acid (50 ml) was added dropwise under ice-cooling. After the completion of the dropwise addition, the reaction mixture was heated to 80° C. and the mixture was stirred for one hr. After cooling, the precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate and dried under reduced pressure to give white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2cccnc2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 200 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg of nicotinoyl chloride*HCl. The following was obtained: 57. C18H18N4O3 (338.37) MS(ESI) 339 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH2:31][CH2:30][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 99.7 %

Procedure:
To a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 57, step C) (10.0 g, 23.27 mmol) and 1,4-dioxane (400 mL) was added MeOH (˜100 mL) to enhance solubility. Methyl vinyl sulfone (6.1 mL, 69.8 mmol) and Na2CO3 (7.4 g, 69.8 mmol) were added and the resultant mixture was heated at 80° C. overnight (˜16 h). LCMS indicated that the reaction had gone to completion. The solvent was evaporated and the residue was taken up in DCM (300 mL) and filtered to remove salts. The filtrate was concentrated in vacuo to afford the title compound of step A (9.9 g, >95%) which was carried forward with no further purification. MS (ES+, m/z) 427 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][C@H:28]1[CH2:33][C@@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:30]4[CH2:31][C@H:32]([CH3:34])[CH2:33][C@H:28]([CH3:27])[CH2:29]4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: C[C@@H]1CNC[C@H](C)C1
Product: C[C@@H]1C[C@H](C)CN(Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1

Procedure:
Prepared analogously to Example 1.2.c. from (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide and cis-3,5-dimethylpiperidine. Yield: 30 mg (30% of theory); melting point: 217° C.-218° C.; C29H31ClN2O (M=459.03); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461.
Reaction SMILES: [C:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12](N=CC3C=CC=CC=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(COC2C=CC=CC=2)C=CC=CC=1.[CH2:37]([N:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C>[C:51]1([N:44]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:45]2[CH:46]=[CH:47][C:48]([N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:49][CH:50]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: C(=Nc1ccc(N=Cc2ccccc2)cc1)c1ccccc1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(COc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: c1ccc(CN(c2ccccc2)c2ccc(N(Cc3ccccc3)c3ccccc3)cc2)cc1

Procedure:
N,N'-Bis(phenylmethylene)benzene-1,4-diamine (1.42 g, 0.005 mol) and phenylmethoxybenzene (1.84 g, 0.010 mol) were heated in Na/DMF (1 g: 50 mL) at 100° C. for 1 hr. Similar workup as for the preparation of benzyldiphenylamine and chromatography on silica using petroleum ether/chloroform 4:1 as eluent gave 0.35 g (16%) mp 149°-51° C. from ethyl acetate. 1H NMR (200 MHz, CDCl3) δ (assignment): 4.96 (s, 4H, PhCH2N-), 6.80-6.97 (m, 6H, aromatic), 7.05 (s, 4H, (PhCH2 (Ph)N)2C6II4), 7.16-7.33 (m, 14H, aromatic). MS [m/e (70 eV, % of base peak)] (PhCH2 (Ph)N)2C6H4 440 (M+., 25.4), 349 (M+. -C7H7., 24.5), 91 (C7H7+, 100). HRMS (m/z) for C32H28N2 (M+.) calcd. 440.225, found 440.227.
Reaction SMILES: C([N:8]1[C:12]2[C:13](=[O:37])[N:14]([CH3:36])[CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=3[O:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:11]=2[CH:10]=[C:9]1[C:38]([O:40][CH2:41][CH3:42])=[O:39])C1C=CC=CC=1.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O.FC(F)(F)C(O)=O>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[O:27][C:18]1[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:17]=1[C:16]1[C:11]2[CH:10]=[C:9]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:8][C:12]=2[C:13](=[O:37])[N:14]([CH3:36])[CH:15]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2n1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Yield: 63 %

Procedure:
A mixture of Example 252e, anisole (1.585 mL, 14.51 mmol) and concentrated sulfuric acid (4.3 mL, 81 mmol) in trifluoroacetic acid (20 mL, 260 mmol) was heated at 90° C. for 4 hours. Excess trifluoroacetic acid was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (2×200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), followed by saturated aqueous sodium chloride (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was taken into methanol (50 mL) and the resulting solid was filtered, rinsed with methanol, and dried to provide the title compound (3.1 g, 63% yield).
Reaction SMILES: [NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:21])[NH:10]2)[C:2]([CH3:4])=[O:3].[N+](C1C(OCCCCBr)=CC=C2C=1C=CC(=O)N2)([O-])=O.C(OC(=O)C)(=O)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(=O)C.[Zn]>[NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:55][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:21])[NH:10]2)[C:2]([CH3:4])=[O:3]
Reactant: Sc1ccccc1
Reactant: CC(=O)Nc1c(OCCCCBr)ccc2[nH]c(=O)ccc12
Agent: O=c1ccc2c([N+](=O)[O-])c(OCCCCBr)ccc2[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(OCCCCSc2ccccc2)ccc2[nH]c(=O)ccc12

Procedure:
Prepared analogous to Example 122 from 5-acetamino-6-(4-bromo-butoxy)-carbostyril [prepared by reduction with zinc in acetic acid of 5-nitro-6-(4-bromo-butoxy)-carbostyril in the presence of acetic acid anhydride] and thiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12](Br)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)O1>C(COC)OC.O>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CNc2ncc(-c3cccnc3)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Temperature: 120 °C

Procedure:
A solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine (50 mg, 0.116 mmol) in dimethoxyethane (0.5 mL) and water (0.5 mL) was degassed with nitrogen while adding NaHCO3 (30 mg, 0.347 mmol), and palladium tetrakis triphenylphosphine (13 mg, 0.012 mmol). 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (28 mg, 174 mmol) was added under nitrogen and the mixture was heated to 120° C. overnight. The reaction mixture was concentrated and taken up in ethyl acetate, filtered through silica with ethyl acetate eluant, and the filtrate concentrated to provide N-(4-methoxybenzyl)-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)-5-(pyridin-3-yl)pyridin-2-amine, which was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: Cc1ccc(CN)o1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=374.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-methoxybenzylamine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[OH:22]>C(O)(=O)C>[OH:13][C:9]1([C:19]2[CH:20]=[C:15]([CH3:14])[C:16]([OH:22])=[CH:17][C:18]=2[CH3:21])[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: Cc1ccc(C)c(O)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC(=O)O
Product: Cc1cc(C2(O)C(=O)c3ccccc3C2=O)c(C)cc1O
Yield: 8.2 %

Procedure:
To a solution of ninhydrin (1.00 g, 5.6 mmol) in glacial acetic acid (20 ml) was added 2,5-dimethyl phenol (0.68 g, 5.6 mmol), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound (0.13 g, 8%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:10]=[C:9]([OH:17])[C:6]=2[C:7]=1[CH3:8])C.[OH-:18].[K+].[OH2:20]>>[CH3:8][C:7]1[C:6]2[C:9]([OH:17])=[CH:10][CH:11]=[C:12]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]=2[O:4][C:3]=1[C:1]([OH:20])=[O:18]
Reactant: CCc1oc2c(C(C)(C)C)ccc(O)c2c1C
Reactant: O
Reactant: [OH-]
Agent: [K+]
Product: Cc1c(C(=O)O)oc2c(C(C)(C)C)ccc(O)c12

Procedure:
Ethyl 3-methyl-4-hydroxy-7-tert-butylbenzofuran (0.405 g, 1.47 mmol) was saponified in a solution of KOH (0.247 g, 4.41 mmol) in refluxing water (10 mL) for two hours. Acidification of the cooled mixture led to precipitation of the product. 3-Methyl-4-hydroxy-7-tert-butylbenzofuran-2-carboxylic acid, compound 8, was collected by filtration and vacuum dried. This material was decarboxylated without further purification, mp 219°-222° C.; 1H NMR (DMSO-d6) d 1.38 (9H, s), 2.64 (3H, s), 6.55 (1H, d, J=8 Hz), 7.07 (1H, d, J=8 Hz), 9.66 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:15]=[C:14]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:54]1[C:59](=[O:60])[CH2:58][CH2:57][C:55]1=[O:56])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:56]=[C:55]1[CH2:57][CH2:58][C:59](=[O:60])[N:54]1[O:11][C:10](=[O:12])[C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:13]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:40]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
5-(15-tert-Butoxycarbonyl-pentadecanoylamino)-isophthalic acid mono-tert-butyl ester (140 mg, 0.25 mmol) was dissolved in dry THF (3.5 ml). TSTU (95 mg, 0.30 mmol) and DIPEA (70 ul, 0.30 mmol) were added. The mixture was stirred at RT under nitrogen over the week-end. The reaction mixture was almost dry. EtOAc was added and the precipitate was removed by filtration. The filtrate was extracted with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give the title compound as a syrup containing a trace of an impurity in a quantitative yield (0.165 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reaction time: 16 h

Procedure:
26.1 g (0.166 mole) of 1-bromo-3-chloropropane and 33.6 g (0.333 mole) of triethylamine are added to 30.0 g (0.166 mole) of 1-(4-fluorophenyl)-piperazine in 50 ml of tetrahydrofuran. The reaction mixture is stirred for 16 hours at from 60° to 65° C., cooled and filtered, the solvent is stripped off under reduced pressure, and the crude product is distilled under reduced pressure from an oil pump. The product distils at 135°-145° C./0.05 mm Hg in a yield of 30.0 g (70%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](=[S:14])[NH2:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15]I>CC(C)=O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([S:14][CH3:15])=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CI
Reactant: CCCCCNc1nc[nH]c1C(N)=S
Solvent: CC(C)=O
Product: CCCCCNc1nc[nH]c1C(=N)SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
To a solution of 4-(pentylamino)-1H-imidazole-5-carbothioamide (1.0 g, 4.7 mmol) in acetone (40 mL) was added methyl iodide (0.80 g, 5.6 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water and ethyl acetate. The organic layer was washed with water and brine, dried and concentrated to yield the crude product (1.2 g), which was used for next step without further purification. LCMS calculated for C10H19N4S (M+H): 227.1. found: 227.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11](=[O:26])/[CH:12]=[CH:13]/[C:14]2[S:24][C:23]3[N:25]4[C:16](=[CH:17][N:18]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH2:5][CH2:4]1.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:31]1([CH2:30][CH2:29][CH2:28][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11](=[O:26])/[CH:12]=[CH:13]/[C:14]3[S:24][C:23]4[N:25]5[C:16](=[CH:17][N:18]=[C:19]5[CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH2:5][CH2:4]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)CCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)CCC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.362 g (0.878 mM) of (E)-5-(piperidin-4-yl]-1-(5-thia-1,8b-diazaacenaphthylen-4-yl)-1-penten-3-one dihydrochloride, 0.26 g (1.32 mM) of 1-bromo-3-phenylpropane, and 0.43 ml (3.07 mM) of triethylamine in 30 ml of ethanol was refluxed for 1 day. The reaction mixture was then poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 9/1) to provide the title compound.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2>C(#N)C>[Br-:8].[CH2:1]([N+:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=[O:17])[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN2CCC1CC2
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: O=C1C[N+]2(Cc3ccccc3)CCC1CC2
Product: [Br-]
Yield: 93.4 %

Procedure:
40.4 g (236 mmol) of benzyl bromide was added dropwise over 15 minutes to 29.5 g (236 mmol) of 3-quinuclidinone in 120 ml of acetonitrile and the suspension formed was filtered through a frit after 2 hours at 25° C. Washing with n-hexane (2×50 ml) and drying gave 65.3 g (93 percent) of 1-benzyl-3-oxoquinuclidinium bromide in the form of a white crystalline solid. Other data concerning the product was: ##EQU4##