Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([CH3:12])[NH:6][C:5]1=[O:13])=[N+:2]=[N-:3].I[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>>[C:19]([O:18][C:16]([CH2:15][N:6]1[CH:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:4]([N:1]=[N+:2]=[N-:3])[C:5]1=[O:13])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1CCCCC(N=[N+]=[N-])C(=O)N1
Reactant: CC(C)(C)OC(=O)CI
Agent: [H-]
Agent: [Na+]
Product: CC1CCCCC(N=[N+]=[N-])C(=O)N1CC(=O)OC(C)(C)C

Procedure:
React 5.65 g of this azide with 7.9 g t-butyl iodoacetate and 0.82 g sodium hydride as described in Example 1 to obtain 1-t-butoxycarbonylmethyl-3-azido-8-methylperhydroazocin-2-one, which can be purified by chromatography over silica gel. NMR (CCl4, TMS): δ 1.0-2.2 (m); δ 1.3 (d); δ 1.45 (s); δ 3.45 (d, J=16h3); δ 3.95 (d, J-16h3); δ 4.3-5.1 (m).
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][N:21]4S(C4C=C(Cl)C=CC=4OC)(=O)=O)=[CH:17][CH:16]=3)=[O:14])=[CH:8][CH:7]=2)=[N:4]N=N1.NC1C=CC(C#N)=CC=1>>[C:5]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:11]=1)#[N:4]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(-c4nnn[nH]4)cc3)cc21
Agent: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide, MS (ISP), m/e=509.1 (M−H), was prepared in analogy to example 13, steps 1 to 4. Step 1 was performed using 4-amino-benzonitrile and yielded 1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide which was reduced to 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide in step 2. This was coupled with 5-chloro-2-methoxy benzenesulfonyl chloride in step 3, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide, which was converted to 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide by reaction with ammonium azide in step 4.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4].[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)#[N:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C.CCCCCC>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[C:29]#[N:30])[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)[nH]c(=O)c21
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture consisting of 100 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate, 60 mg of 2-cyanobenzyl bromide, 68 mg of anhydrous potassium carbonate, and 1 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. Ethyl acetate/hexane (1/1) and water were added to the reaction solution. The insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30 to 50% ethyl acetate/hexane to give 50 mg of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][N:4]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1>>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:4]2[CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:7]=[CH:8][C:3]2=[O:2])=[CH:20][CH:21]=1
Reactant: OCc1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc(OC)nc2)cc1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(CO)cc3)c2)cc1
Yield: 80.4 %

Procedure:
According to Scheme 4 Step 1: The title compound was prepared according to Example 6 Step 2, from 2-methoxy-5-(4-methoxyphenyl)pyridine (1 eq, 4.60 mmol, 1.00 g) and (4-(bromomethyl)phenyl)methanol (1.1 eq, 5.10 mmol 1.00 g). Reaction conditions: 5 hours at 70° C. and room temperature overnight. The residue was triturated with pentane, yielding the title compound (3.70 mmol, 1.20 g, 80%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.29 ml) and methanesulfonyl chloride (0.12 ml) were added to a solution of ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-(2-phenoxyethyl)propionate (503 mg), which is the product of Reference example 3(f), in anhydrous dichloromethane (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours. At the end of this time the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on silica gel column using hexane/ethyl acetate=2/1-3/2 as the eluant to afford the desired compound (632 mg) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:12][C:9]1[CH:8]=[C:4]([C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:25][C@H:14]23)=[O:7])[CH:3]=[C:2]([Cl:1])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 32 %

Procedure:
The title compound is prepared from 3,5-dichloro-4-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 32% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=362/364/366 (Cl) [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>[Pd].CC(N(C)C)=O>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1
Yield: 51.4 %

Procedure:
10% Palladium on charcoal (0.5g) was added to a solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6g, 30mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (11.2 g, 30 mmol) in dimethylacetamide (10 ml)and tributylamine (10 ml, 42 mmol) at 110° C. After 90 min. the solution was filtered and diluted with isopropanol (0.31) and chilled in a freezer. The product was filtered off, dried and dissolved in boiling formic acid (100 ml). The solution was filtered and water (65 ml) was added. After cooling to refrigerator temperature the product was filtered off and dried to yield 7.2 g (51% ) product
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1([NH2:26])[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:17]1([NH:26][C:14]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=2)=[O:15])[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=[CH:18]1
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: Nn1ccc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nn1ccc2cccnc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1.13 mmol) in EtOAc (20 mL) is added to a stirred solution of pyrrolo[2,3-b]pyridin-1-ylamine (1.13 mmol) and K2CO3 (1.13 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridin-1-ylamide (305 mg, 81%) as a solid. MS: 334 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.57 (d, H) 7.13-7.55 (m, 4H), 7.99 (m, H), 8.10-8.40 (m, 3H), 9.27 (s, 2H), 12.57 (br, N—H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH2:27]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([CH:40]=O)=[N:37]2)=[CH:32][C:31]=1[F:42])[CH3:28]>C(O)C>[CH2:27]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36](/[CH:40]=[N:11]/[NH:10][C:7]3[N:6]=[CH:5][C:4]([C@@H:3]([N:12]4[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]4)[C:2]([F:25])([F:1])[F:26])=[CH:9][CH:8]=3)=[N:37]2)=[CH:32][C:31]=1[F:42])[CH3:28]
Reactant: CCOc1cc2nc(C=O)ccc2cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: CCOc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F

Procedure:
tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (240 mg, 0.639 mmol) and 7-ethoxy-6-fluoroquinoline-2-carbaldehyde (140 mg, 0.639 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1>[Pd].CCOC(C)=O.CO>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN1CCC(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)CC1
Yield: 70.9 %

Procedure:
A solution of 1-methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (0.20 g, 0.560 mmol) in 2:1 EtOAc/MeOH (15 mL) was treated with Palladium on carbon (50% wet) (0.066 g, 0.056 mmol) was hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with MeOH and the filtrate concentrated to dryness to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide (130 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.13 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.9, 3.0 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.01 (s, 2H), 2.77 (m, 2H), 2.39 (m, 1H), 2.14 (s, 3H), 1.83 (m, 2H), 1.67 (m, 2H), 1.57 (m, 2H); MS (ESI) m/z: 328.2 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 2-naphthaldehyde and acetophenone, 3-(2-naphthalenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-].[K+]>C1COCC1.O>[CH:1]([C:4]1[C:12]([C:13]([OH:16])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn2ccccc2c1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nn2ccccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.2 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (1.5 g, 1 equivalent) and potassium permanganate (2.9 g, 2.1 equivalents) in 10 mL of THF was stirred at room temperature for 2 days. A solution of potassium hydroxide (2.2 g, 5 equivalents) in 10 mL of water was added and the resulting solution was stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble solids and the filtrate was extracted to remove unreacted aldehyde. The remaining aqueous solution was acidified with concentrated HCl and the precipitates were collected by filtration and dried under reduced pressure to give 2-isopropylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.98 g, 60% yield) as a solid. Compound 1079.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][S:12][CH3:13])[CH:6]=[CH:5][C:4]=1[N+:14]([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][S:12][CH3:13])[CH:6]=[CH:5][C:4]=1[NH2:14]
Reactant: COc1cc(OCCSC)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(OCCSC)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Step B A suspension of 2-methoxy-4-(2-methylsulfanyl-ethoxy)-1-nitro-benzene (0.25 g, 1.0 mmol) in methanol (8 mL) was added an aqueous solution (4 mL) of NH4Cl (0.55 g, 10 mmol), followed by activated Zinc (Aldrich, 0.67 g, 10 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was filtered through a short pad of celite. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-methoxy-4-(2-methylsulfanyl-ethoxy)-phenylamine as a brown oil (0.2 g, 91%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:19]=[CH:18]2>>[CH3:29][CH:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH:16]=2)[CH:21]=1)[C:26]([OH:28])=[O:27]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCCCCCI
Product: CCCCCCCCCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodododecane and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 96°-97° C.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of methyl 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (3.60 g) in tetrahydrofuran (100 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.36 g) at room temperature. After stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (3.60 g, yield 100%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: COc1cccc(O)c1
Product: COc1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-methoxyphenol: ESMS m/e: 564.6 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH:20][S:21]([O-:23])=[O:22].[Na+:24]>CCO.O>[Na+:24].[OH:17][CH:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:19][CH:18]=1)[S:21]([O-:23])(=[O:22])=[O:20]
Reactant: O=S([O-])O
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (20.0 g, 76.9 mmol) in EtOH (200 mL) was stirred at room temperature for 15 min. To the resulting solution was added a solution of NaHSO3 (9.6 g) in H2O (25 mL), dropwise over 30 min. The resulting suspension was stirred at room temperature for 2 h, then cooled to 0° C. and stirred for 3 h, adding EtOH periodically (total 200 mL) to aid stirring. A precipitate formed and was collected by suction filtration through a glass frit lined with filter paper. The filter cake was washed with hexane (1×50 mL), and dried under vacuum for 16 h to yield the title compound as a white solid.
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H]2CC[C@H](CC(OC)=O)CC2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].O=C(NC1C=C[C:35]([S:38](CCC)(=[O:40])=[O:39])=[CH:34][CH:33]=1)C(OC)=O>>[NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:38]([CH2:35][CH2:34][CH3:33])(=[O:40])=[O:39])=[CH:11][CH:12]=1)=[O:5])[NH2:2]
Reactant: CCCS(=O)(=O)c1ccc(NC(=O)C(=O)OC)cc1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Product: CCCS(=O)(=O)c1ccc(NC(=O)C(=O)NN)cc1

Procedure:
The procedure described for Intermediate 43 (part iv) was followed starting with methyl oxo{[4-(propylsulphonyl)phenyl]amino}acetate to give the title compound (Intermediate 97); 1H NMR δ 0.85-0.97 (m, 3H), 1.46-1.65 (m, 2H), 3.18-3.27 (m, 2H), 4.77 (s, 2H), 7.85 (d, 2H), 8.10 (d, 2H), 10.44 (s, 1H), 11.09 (s, 1H); MS m/e MH+ 286.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](SC)=[N:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][NH2:26]>>[CH2:1]([N:8]1[C:16]2/[C:15](=[N:25]/[NH2:26])/[NH:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCn1c(=O)nc(SC)c2c1ncn2Cc1ccccc1
Reactant: NN
Product: CCCCCn1c(=O)[nH]/c(=N\N)c2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
7-Benzyl-6-(methylthio)-3-pentyl-3,7-dihydro-2H-purin-2-one (1.2 g, 3.5 mmol) and hydrazine (10 mL, 100 mmol) were mixed. After being stirred at 100° C. overnight, the solution was concentrated in vacuum. The residue was dissolved in DMSO and purified using preparative LCMS. The product fractions were collected and lyophilized to provide the product as a white powder (0.56 g, 60% yield). LCMS calculated for C17H23N6O (M+H): 327.2; found: 327.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.O>C1COCC1>[C:11]([C:9]1[N:8]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CO)nn1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
To a solution of compound 3h (0.8 g, 2.28 mmol) in 25 mL of THF was added LiAlH4 (0.14 g, 3.65 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAc (50 mL) and water (50 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes=7/3) to give the titled compound (0.56 g, 80% yield) as a white solid. mp 143.0-146.5° C. 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H), 6.26 (s, 1H), 5.10 (t, J=6 Hz, 1H), 4.39 (d, J=6 Hz, 2H), 3.32 (s, 3H), 1.14 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[C:28]([O-:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([O-:33])=[O:32]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 60 °C

Procedure:
A reactor was charged with 0.101 g (S)-zopiclone and 0.040 g maleic acid. The mixture was charged with 18 g ethanol, and agitated. The slurry was heated to 60° C. and aged for 90 minutes. The slurry was cooled to 20° C. and aged for 60 minutes. The reaction was filtered, washed once with 0.5 g ethanol, dried in vacuo at approximately 50° C. for approximately 6 hr, and provided the titled compound in 76% yield.