Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[S:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>CN(C)C=O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:4]1[C:5](=[O:7])[CH2:6][S:2][C:3]1=[O:8]
Reactant: O=C1CSC(=O)N1
Reactant: BrCCCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
The 2,4-thiazolidinedione sodium salt (13.91 g., 0.1 mole) is added to a solution of 1,4-dibromobutane (64.77 g., 0.3 mole) in 500 ml. of dry dimethylformamide. After stirring the mixture at room temperature for a 16 hr. period, the resulting clear solution is concentrated in vacuo and residual material dissolved in chloroform, filtered, and concentrated in vacuo to an amber oil. Distillation of the oil affords 20.62 g. (81% yield) of 3-(4-bromobutyl)-2,4-thiazolidinedione, b.p. 105°-115° C. at 0.02 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@@H]3CCOC3)c2)n1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide (150 mg, 0.49 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (120 mg, 0.49 mmol), bromotris(triphenylphosphine)copper (92 mg, 0.10 mmol) and caesium carbonate (484 mg, 1.48 mmol) in acetonitrile (7 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The solid was filtered off, the solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue. The organic phase was washed with water (10 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the title compound as a white solid (86 mg). 1H NMR δ (CDCl3): 2.10-2.17 (m, 1H), 2.19-2.25 (m, 1H), 2.32-2.38 (m, 2H), 3.76 (s, 3H), 3.87-3.92 (m, 1H), 3.95-4.01 (m, 3H), 4.24 (t, 2H), 4.71 (t, 2H), 4.97 (t, 1H), 6.73 (t, 1H), 6.81 (s, 1H), 7.11 (s, 1H), 7.24 (s, 1H), 7.27-7.30 (m, 1H), 7.36-7.39 (m, 1H), 8.12 (d, 1H), 8.31 (d, 1H), 8.72 (s, 1H); m/z 464 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH2:23]>>[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NCC(O)CN
Product: NCC(O)CNc1cc(-c2ccc(Cl)cc2)nc2ccccc12

Procedure:
The title compound, m.p. 283-287° C. and MS: m/e=328.2 (M+H+), was prepared from 4-chloro-2-(4-chloro-phenyl)-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[C:16]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][CH:30]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(OC(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Chlorobenzene (7 ml) was added to 4-chloro-6,7-dimethoxyquinazoline (2.5 g) and 4-hydroxyphenyl benzoate (4.78 g), and the mixture was stirred at 140° C. overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by filtration and was washed to give the title compound (3.49 g, yield 78%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH:33]=[N:32][NH:31][C:30]2=[O:34])[CH2:25][CH2:24]1.CO>ClCCl>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:24][CH2:25][CH:26]([N:29]3[C:30](=[O:34])[NH:31][N:32]=[CH:33]3)[CH2:27][CH2:28]1)[CH:11]=[CH:10]2
Reactant: O=c1[nH]ncn1C1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Solvent: ClCCl
Solvent: CO
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC(n4cn[nH]c4=O)CC3)ccc12

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (150 mg) and 2,4-dihydro-4(4-piperidinyl)-3H-1,2,4-triazol-3-one Example 64 (c)) (225 mg). Methanol (10 mL) and dichloromethane (10 mL) were added to the reaction mixture and the solid was collected by filtration to afford the title compound (40 mg).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:16]>CCO>[CH3:14][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N:1]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:3]=[N:2]2)[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(C(=O)O)cc(N=[N+]=[N-])c1C
Reactant: C#Cc1cccnc1
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(-n2cc(-c3cccnc3)nn2)c1C
Yield: 32.7 %

Procedure:
A suspension of 100 mg (0.52 mmol) of 3-azido-4,5-dimethyl benzoic acid (U.S. Ser. No. 04/102,492), 54 mg (0.52 mmol) of 3-ethynyl pyridine, and 200 μL of EtOH was heated to 120° C. in a sealed tube for 12 h. The mixture was cooled and diluted with 500 μL of EtOH. The mixture was filtered and the solids were washed with EtOH (3×0.5 mL). The solids were dried to provide 50 mg of 3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1.[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:25]([O:1][CH2:2][C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)(=[O:26])[CH3:24]
Reactant: C[C@]12CCC(=O)CC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6α-hydroxymethylandrostane-3,17-dione (II-an, Prepn. 14, 42 mg) in pyridine (1.5 mL) at 0° C., DMAP (1 mg) and Ac2O were added. After stirring overnight at room temperature, the solution was evaporated. The residue was treated with 1N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound II-ao (91%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.97 (m, 2H), 2.53-0.80 (m, 21H), 1.99 (m, 3H), 1.13 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])=[CH:10][CH:11]=1.[OH:20][P:21]([O-:24])([OH:23])=[O:22].[OH:25][P:26]([O-:29])([O-:28])=[O:27].[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+]>>[CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])=[CH:8][CH:7]=1.[CH:11]1([O:27][P:26]([OH:29])([OH:28])=[O:25])[CH:10]([O:22][P:21]([OH:24])([OH:23])=[O:20])[CH:9]([O:27][P:26]([OH:29])([OH:28])=[O:25])[CH:8]([O:22][P:21]([OH:24])([OH:23])=[O:20])[CH:7]([O:27][P:26]([OH:29])([OH:28])=[O:25])[CH:6]1[O:22][P:21]([OH:24])([OH:23])=[O:20]
Reactant: O=P([O-])(O)O
Reactant: O=P([O-])([O-])O
Agent: CCCCNc1ccc(C(=O)OCCN(C)C)cc1
Agent: [Cl-]
Agent: [K+]
Product: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O

Procedure:
The film thus obtained is melted and compression molded at 80° C. to give a film about 0.5 mm thick. The film is incubated in phosphate buffered saline (containing 0.02% sodium azide) at pH 7.4 and 37° C., and the buffer solution is assayed periodically by UV to determine the amount of tetracaine released.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:13]3[CH2:18][CH2:17][N:16]([CH:19]([CH2:24][O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:20](OC)=[O:21])[CH2:15][CH2:14]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:13]3[CH2:18][CH2:17][N:16]([CH:19]([CH2:24][O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:20][OH:21])[CH2:15][CH2:14]3)[C:33](=[O:34])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(COCc1ccccc1)N1CCC(N(Cc2cc3c(cn2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(C(CO)COCc2ccccc2)CC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of methyl 2-[4-((2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-3-[(phenylmethyl)oxy]propanoate (618 mg, 1.141 mmol) in dry THF (8 ml) at −78° C. under Ar was added LiAlH4 (1.312 ml, 1.312 mmol) dropwise. The reaction mixture was allowed to warm to ˜−10° C. over 2 h. The mixture was then stirred at 0° C. for 2 h before addition of water (0.1 ml), then sodium hydroxide (0.18 ml, 0.360 mmol) and then water (0.2 ml). The mixture was then stirred for a further 2 h at rt. The resulting mixture was filtered and washed with THF (100 ml). The combined filtrate and washings were evaporated under reduced pressure to afford the product (0.519 g, 89% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O>C(O)C>[OH:3][N:2]=[CH:4][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C=NO
Temperature: 0 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
Hydroxylamine hydrochloride (4.3 grams, 0.062 mole) was added to a cold solution of 5-formyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (7 grams, 0.031 mole) in absolute ethanol (40 ml). The reaction mixture was stirred in the cold for thirty minutes, then at room temperature for 16 hours. The reaction mixture was then poured over ice-water, and the precipitated product was separated, dried, and recrystallized from toluene, yielding 3 grams of 5-(hydroxyiminomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester, m.p., 105° C.-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 200 mg (0.807 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (prepared from 6-chloro indole and trifluoroacetic anhydride, described in U.S. 2004067939 A1) in 8 ml CH2Cl2, 293 mg (1.615 mmol) Cu(OAc)2, 0.26 ml (3.23 mmol) pyridine and 383 mg (2.42 mmol) 3,5-difluorophenyl boronic acid were added. The reaction mixture was stirred at RT overnight, filtered on decalit, and concentrated under vacuo. Column chromatography over silica (hexane followed by 1:9 ethyl acetate hexane) provided 206 mg (71%) of 1-[6-chloro-1-(3,5-difluoro-phenyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone as a light brown solid. This compound was put in suspension in 10 ml H2O and 1.2 g NaOH was added. The reaction mixture was stirred at 70° C. for 2 days, cooled down to RT, and acidified with aqueous HCl (1N) until ph=1. The product was extracted with CH2Cl2, and the organic phase dried over Na2SO4. Evaporation of the solvent under vacuo afforded 120 mg (70%) of 6-chloro-1-(3,5-difluoro-phenyl)-1H-indole-3-carboxylic acid as a white solid.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16](=O)[CH:15]([CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH3:24][NH:25][NH2:26]>C1COCC1.O>[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2=[N:26][N:25]([CH3:24])[C:21](=[O:23])[CH2:20][CH:15]2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(CC(=O)O)CC1
Reactant: CNN
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN1N=C2CCN(C(=O)OC(C)(C)C)CCC2CC1=O

Procedure:
36 mL acetic acid was added to 10.5 g 4-carboxymethyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester in 75 mL THF at 5° C. 3.1 mL methylhydrazine was added to the mixture and refluxed for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine. The crude product was purified by column chromatography on silica gel to yield 6.9 g of the desired product. (M+H)+: 282
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:24][N:25]([CH2:27][CH:28]([OH:38])[CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>CN1C(=O)CCC1>[CH3:26][N:25]([CH2:27][CH:28]([OH:38])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35][C:2]2[N:7]=[C:6]([N:8]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)[CH3:24]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1nccc(N(CCc2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N(CCc3ccccc3)c3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 35.7 %

Procedure:
2-Chloro-4-(N-(2-phenylethyl)anilino)pyrimidine (Reference Example E-3; 270 mg, 0.87 mmol) was dissolved in NMP (2 ml), 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 222 mg, 0.90 mmol) was added and the mixture heated at 120° C. for 12 hours. The solvent was evaporated, the residue was resolubilized in methanol/ammonia 6M and evaporated again to dryness. The resulting solid was purified by flash chromatography using increasingly polar solvent mixtures starting with DCM and ending with DCM/methanol with 10% ammonia (87.5/12.5). Evaporation of the solvent gave a foam which was triturated in ether to give the title product as a white solid (150 mg, 36%). NMR: (400 MHz, 353K) 2.30 (s, 6H), 2.50 (m, 2H), 2.90 (m, 2H), 3.80 (m, 1H), 3.85 (m, 1H), 3.95 (br s, 1H), 4.10 (m, 2H), 5.00 (br s, 1H), 5.50 (d, 1H), 6.70 (d, 2H), 7.15 (m, 3H), 7.25(m, 4H), 7.35 (t, 1H), 7.50 (t, 2H), 7.60 (d, 2H), 7.80 (d, 1H), 8.85 (s, 1H), M.S.: (ES+) 484 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10](O)[C:9]=2[C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[NH:10][C:9]=2[C:18]([F:21])([F:19])[F:20])=[CH:6][CH:7]=1
Reactant: On1c(C(F)(F)F)cc(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)c(C(F)(F)F)[nH]1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Zinc dust (20 g, 0.3 mol) is added to a solution of 3-(p-chlorophenyl)-2,5-bis(trifluoromethyl)1-hydroxypyrrole (7.5 g, 0.023 mol) and acetic acid (50 mL). The reaction mixture is refluxed for 1/2 hour, cooled to room temperature, filtered to remove solids, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a pale red liquid (6.8 g). A portion of the red liquid (1.6 g) is chromatographed using silica gel and eluted with methylene chloride to give the title product as a colorless liquid (1.1 ). Identified by IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]1=[O:17].[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:3]1=[O:17]
Reactant: CN1CC=CC[C@H](NC(=O)OC(C)(C)C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Yield: 69.3 %

Procedure:
To a degassed solution of 1,1-dimethylethyl [(3S)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (Example 94) (680 mg, 2.8 mmol) in MeOH (20 mL) was added 10% Pd/C (100 mg) and the resulting suspension was stirred overnight under a balloon of hydrogen. Filtration of the catalyst and concentration of the filtrate under reduced pressure yielded 1,1-dimethylethyl [(3S)-1-methyl-2-oxohexahydro-1H-azepin-3-yl]carbamate (470 mg, 88%). LCMS: (M−tBut)+: 186.2.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH:16](O)[CH:17]([CH3:19])[CH3:18])[C:6]=1[CH3:21])(=[O:3])[CH3:2].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]2[O:15][C:17]([CH3:19])([CH3:18])[CH2:16][C:7]=2[C:6]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(C)C)c1C
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Yield: 18.6 %

Procedure:
0.40 g of 4-acetoxy-5-t-butyl-2-(1-hydroxy-2-methylpropyl)-3-methylphenol was dissolved in 10 ml of anhydrous toluene, 0.35 ml of boron trifluoride ethyl ether was added dropwise, and the mixture was stirred at room temperature for a whole day and night. After the reaction was quenched with water, the mixture was extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1%-2% ethyl acetate) to give 70 mg of 5-acetoxy-6-t-butyl-2,2,4-trimethyl-2,3-dihydrobenzofuran as a pale yellow oil (yield 19%).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][SH:9])[CH3:2].[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:17]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][S:3][CH2:1][CH3:2]
Reactant: CCOC(=O)CCCCI
Reactant: CCSCCCCCS
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCSCCCCCSCC

Procedure:
To illustrate the preparation of the dithia-substituted fatty acid ethers, 5-ethylthiopentane thiol can be reacted with sodium hydride and the resulting product reacted with ethyl 5-iodovalerate to yield ethyl 6,12-dithiatetradecanoate. The ester group can then be removed by treatment with alkali metal hydroxide, e.g. NaOH, to produce the desired 6,12-dithiatetradecanoic acid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[O:11][C:12]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:13][N:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([NH:9][C:10]1[O:11][C:12]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[S:21]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])=[N:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1nnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nnc(NCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzaldehyde (101 μl) was added to a solution of 2-amino-5-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-1,3,4-oxadiazole (163 mg) [see Example 32] in tetrahydrofuran (2 ml), followed by acetic acid (172 μl) and sodium triacetoxyborohydride (297 mg). The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 40:60 (in 10% increments), by volume, ethyl acetate:hexane, to afford 2-benzylamino-5-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-1,3,4-oxadiazole (6 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH2:9][C@@H:10]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]1)[CH3:7])[CH3:4].I[CH2:18][C:19]#[C:20][CH2:21][O:22][CH2:23][C:24]#[N:25].[NH4+].[Cl-]>CN(C=O)C>[CH2:3]([O:5][CH:6]([O:8][CH2:9][C@H:10]1[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[N:15]1[CH2:18][C:19]#[C:20][CH2:21][O:22][CH2:23][C:24]#[N:25])[CH3:7])[CH3:4]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1
Reactant: N#CCOCC#CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 600 mg, 15.0 mmol) was added to a solution of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one (from example 50, step 1, 3.00 g, 14.9 mmol) in DMF (20 mL) at 0° C. After 1 h at 0° C., (4-iodo-but-2-ynyloxy)-acetonitrile (3.50 g, 14.9 mmol) in DMF (10 mL) was added via cannula and the reaction was allowed to warm to rt. After 16.5 h at rt, the reaction was treated with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (2×100 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→50% EtOAc/CH2Cl2, gradient) afforded 1.83 g (40%) of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetonitrile.