Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[C:7](=O)[NH:8][CH2:9][CH2:10][N:5]2[CH2:4][CH2:3][S:2]1(=[O:13])=[O:12].Cl>C1COCC1>[CH2:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[CH2:4][CH2:3][S:2]1(=[O:13])=[O:12]
Reactant: O=C1NCCN2CCS(=O)(=O)CC12
Agent: Cl
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCNCC2C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 111.6 %

Procedure:
To a suspension of hexahydropyrazino[2,1-c][1,4]thiazin-9(6H)-one 2,2-dioxide (D18; 165 mg, 0.81 mmol) in 1 ml of anhydrous THF were added successive aliquots of a 1M solution of borane THF complex in THF (total 20.4 ml, 20.4 mmol) and the reaction stirred at room temperature and 50° C., until disappearance of the starting material. Hydrochloric acid (5M, 2 ml) was added to the solution and stirring was continued at 50° C. for 12 h. The solvent was removed under reduced pressure and the residue loaded on a SCX cartridge, washed with methanol and eluted with 0.5M methanolic ammonia. The basic fractions were collected and the solvent removed leaving 172 mg of the target product, partially contaminated by the starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12](OCC)=[O:13])=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][OH:13])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(CO)cc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 114.3 %

Procedure:
A solution of ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (9.21 g) in THF (55 mL) was added dropwise to a solution of lithium aluminum hydride (2.08 g) in THF (110 mL) at 5° C., and the mixture was stirred at room temperature for 4.5 hr. To the reaction mixture was added sodium sulfate decahydrate (20.4 g), and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off and washed with THF. The filtrate was concentrated under reduced pressure to dryness to give the title compound (8.50 g, yield 100%) as a yellow solid.
Reaction SMILES: C(O[CH:4]=[CH2:5])=C.[C:6]1([CH2:11][SH:12])[S:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH2:11][S:12][CH2:11][C:6]2[S:10][CH:5]=[CH:4][CH:7]=2)[S:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=COC=C
Reactant: SCc1cccs1
Product: c1csc(CSCc2cccs2)c1

Procedure:
f. Dithenyl sulfide was prepared by the same method as used for compound (1) b. (diethenyl ether) of Group X above, except that thenylmercaptan was used instead of thenyl alcohol. The product has a b.p. of 118°C./0.04 mm. Hg.
Reaction SMILES: C1(O[C:8](=[O:18])[NH:9][C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:17][O:16][C:11]1[C:10]([NH:9][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1ncccc1NC(=O)Oc1ccccc1
Product: COc1ccc(N2CCN(C(=O)Nc3cccnc3OC)CC2)cc1
Yield: 85 %

Procedure:
Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([CH2:20][OH:21])[CH2:15][CH2:14][C:13]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:12][CH2:11]1>CN(C=O)C.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][O:19][C:13]21[CH2:14][CH2:15][C:10]1([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:21][CH2:20]1)[CH2:11][CH2:12]2
Reactant: OCC1(c2ccccc2F)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)OCC21CCC2(CC1)OCCO2
Temperature: 110 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
Sodium hydride (80% in mineral oil, 1.53 g, 51 mmol) was stirred in dry DMF (30 ml) as 4'-(2-fluorophenyl)-4'-(hydroxymethyl)spiro[[1,3]-dioxolane-2,1 '-cyclohexane] (D22, 5.44 g, 20 mmol) was added in dry DMF (70 ml). The mixture was stirred under Ar at 110° C. for 6 h, cooled, diluted with ethyl acetate (500 ml), washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (4.83 g, 96%) as a straw-coloured solid.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CCN=C=NCCCN(C)C.Cl.[CH3:57][O:58][CH2:59][CH2:60][NH:61][C:62](=[O:67])[CH2:63][CH2:64][NH:65][CH3:66]>ClCCl.CN(C)C1C=CN=CC=1>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29](=[O:30])[C:31]2[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([N:65]([CH2:64][CH2:63][C:62]([NH:61][CH2:60][CH2:59][O:58][CH3:57])=[O:67])[CH3:66])=[O:35])[CH:32]=2)[CH:11]=1)=[O:9]
Reactant: CNCCC(=O)NCCOC
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Into a 10-mL vial, was placed a solution of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e (80 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL), EDC.HCl (51.1 mg, 0.27 mmol), 4-dimethylaminopyridine (32.4 mg, 0.27 mmol, 2.00 equiv), and N-(2-methoxyethyl)-3-(methylamino)propanamide (31.2 mg, 0.20 mmol, 1.47 equiv). The resulting solution was stirred for 6 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×70 mL of NH4Cl. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. This yielded 50.4 mg (44%) of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide as a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm) δ 8.89 (d, J=5.1 Hz, 1H), 8.43 (t, 1H), 8.31 (s, 1H), 7.94 (t, J=9.3 Hz, 4H), 7.83 (m, 7H), 4.58 (s, 2H), 3.32-3.65 (m, 7H), 3.07-3.17 (m, 6H), 2.85-2.95 (m, 3H), 2.31 (s, 2H), 1.63-1.85 (m, 6H). MS (ES, m/z): 745 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:7]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH:28]C(=O)OC(C)(C)C)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[C:9]#[C:8][C:6]1[CH:5]=[N:4][C:3]2[C:2]([CH:7]=1)=[C:25]1[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][C:26]1=[N:28][C:19]=2[NH2:20]
Reactant: Cc1cc(C)c(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-(mesitylethynyl)picolinonitrile (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol %), and 2N aqueous sodium carbonate solution (3.0 eq.) in toluene/ethanol (4:1, 0.2 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM. The two phases were separated. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give 2-(mesitylethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[ClH:8].[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18](=[NH:21])OC.Cl>CO.C(OCC)C.C(O)C>[ClH:8].[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]1[NH:21][CH:3]=[CH:4][N:5]=1
Reactant: COC(CN)OC
Reactant: COC(=N)c1cc2ccccc2o1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: c1ccc2oc(-c3ncc[nH]3)cc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of aminoacetaldehyde dimethylacetal (7.3 g) and methyl benzofuran-2-carboximidate hydrochloride (13.4 g) in methanol (135 ml) was stirred at 60° C. for 16 hours. The mixture was then evaporated to dryness. Hydrochloric acid (750 ml, 2M) was added and the resulting mixture was stirred at 60° C. for 16 hours. After cooling, the solution was washed with dichloromethane. The aqueous layer was basified with sodium hydroxide and the free base was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. Evaporation of the solvent gave a solid residue which was dissolved in diethyl ether/ethanol. Ethereal HCl was added to solution and the precipitated salt was collected by filtration (12.5 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([S:34][CH:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)=[CH:24][C:6]=43)[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: CC(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (210 mg, 0.541 mmol), 1-isopropylpiperidine-4-thiol (129 mg, 0.812 mmol), Pd2(dba)3 (25 mg, 5 mol %), XantPhos (31 mg, 10 mol %) and DIPEA (380 μl, 2.16 mmol) in dioxane (5 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was then diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 2-15% MeOH in DCM followed by C18, gradient 15-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid/gum (146 mg, 58%). LCMS: RT 2.20 min [M+H]+ 467.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH2:21][O:22][CH3:23])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH2:21][O:22][CH3:23])=[CH:14][C:10]=1[C:11]([NH2:26])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCOCCc1ccc(OCc2ccccc2)c(C(N)=O)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 2-benzyloxy-5-(2-methoxymethoxyethyl)benzoic acid (900 mg) in tetrahydrofuran (25 ml) was added 1,1′-carbonyldiimidazole (507 mg) at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture was added 28% ammonium hydroxide (3 ml), and the resulting mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, crystallization of the residue from hexane and diethyl ether (1/1) gave 2-benzyloxy-5-(2-methoxymethoxyethyl)benzamide (700 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][C:30]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[OH:31])[N:8]=2)[CH2:3]1.C1([O:52][C:53](=O)[NH:54][C:55]2[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=2)C=CC=CC=1>CN1C(=O)CCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)([OH:31])[CH2:29][NH:28][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:53]([NH:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:52])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[CH:33][CH:34]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution comprising: N-((1S,2R,3S,4R)-4-{2-((R)-3-Amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-hydroxy-acetamide (Intermediate ZO; 1 equivalent) and pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB; 1 equivalent) in NMP is stirred at 100° C. for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by column chromatography/crystallisation.
Reaction SMILES: Cl.[C:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH3:3].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl.O>[C:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C

Procedure:
4-Acetylpiperidine hydrochloride (4B-1, 5.0 g, 30.55 mmole) was taken up in CH2Cl2 (150 mL). To this was added Et3N (9.8 mL, 70.27 mmole) and the suspension became a solution. The mixture was cooled to 0° C. to which was added benzyl chloroformate (5.2 mL, 36.66 mmole). After the addition was complete the mixture was warmed to RT. After 18 hr the mixture was diluted with H2O. The layers were separated and the aqueous extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford benzyl 4-acetylpiperidine-1-carboxylate as an off-white solid (4B-2): 1H-NMR (500 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 4.18 (bs, 2H), 2.88 (bs, 2H), 2.49 (m, 1H), 2.17 (s, 3H), 1.86 (bs, 2H), 1.55 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][S:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)(=[O:36])=[O:35])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)NCC2Cc3c(sc(N)c3C(=O)OC(C)(C)C)CO2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (101 mg, 0.35 mmol) in dichloromethane (1 ml) was added pyridine (32 μl, 0.39 mmol) and 4-methoxybenzenesulfonyl chloride (82 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane (2 ml) and subjected to preparative TLC (1:1 hexanes/ethyl acetate) affording 10 mg, (10% ) of 2-amino-5-((4-methoxy-benzenesulfonylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:24])([F:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:3][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([F:24])([F:23])[F:5])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 3.78 ml of thionyl chloride in 30 ml of dichloromethane were slowly added dropwise to a solution of 9.69 g (34.57 mmol) of (4-{2-[4-(trifluoromethyl)phenyl]ethyl}phenyl)methanol in 100 ml of dichloromethane. After the addition had ended, the reaction mixture was warmed to room temperature and stirred at this temperature for two hours. The reaction mixture was then once more cooled to 0° C., and 100 ml of saturated aqueous sodium bicarbonate solution were added slowly and carefully with vigorous stirring until a pH of 6 had been reached. The phases were then separated, and the organic phase was dried over magnesium sulphate, filtered and concentrated to dryness. This gave 8.64 g (28.92 mmol, 84% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2ccc(O)cc2n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nc2ccc(O)cc2n1Cc1ccccc1

Procedure:
1-Benzyl-6-hydroxy-2-amino-1H-benzimidazole was treated with BOC2O in pyridine, followed by hydrolysis with NaOH (aq) to give the title compound; MS m/e 340 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:4][CH:3]=1.Br[C:37]([CH3:43])([CH3:42])[C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][C:37]([CH3:43])([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:3][CH:4]=3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: COC(=O)C(C)(C)Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ncnn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c2ncnn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.70 g), methyl 2-bromo-2-methylpropanoate (7.30 g), cesium carbonate (13.07 g) and N,N-dimethylformamide (20 mL) was stirred at 80° C. overnight. The reaction mixture was poured into 1 M hydrochloric acid (40 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.50 g, quantitative).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C@@H:10]2C[C@H]2CN2C[C@H](C)O[C@H](C)C2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=[O:23].CN(C=O)C1C=CC=CC=1.C(C1SC=CC=1)CCC.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:5]1[S:9][C:8]([CH:10]=[O:23])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1ccc([C@@H]2C[C@H]2CN2C[C@@H](C)O[C@@H](C)C2)s1
Agent: CCCCc1cccs1
Agent: CN(C=O)c1ccccc1
Agent: O=C([O-])[O-]
Product: CCCCc1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
This Example illustrates the preparation of 4-[2-(5-n-butylthiophen-2-yl)-trans-cyclopropylmethyl]-2,6-cis-dimethylmorpholine (Compound No. 8 in Table I). Phosphorus oxychloride (12.02 g, 0.078 mol) was added dropwise to N-methylformanilide (10.62 g, 0.079 mol) and a yellow solid was produced. This was cooled to 0° C. for 1/2 hour, then 2-n-butylthiophene (10 g, 0.071 mol) was added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was poured into ice/water, neutralised with sodium carbonate and extracted into diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulphate and the solvent removed to give a brown oil. Purification by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) gave 5-n-butyl-2-thiophenecarboxaldehyde (11.8 g, 99%). Sodium hydride (6.63 g-50% suspension in oil, 0.138 mol) was washed with petroleum ether, suspended in dry DMSO (100 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (48.72 g, 0.136 mol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-n-butyl-2-thiophenecarboxaldehyde (23 g, 0.137 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give (5-n-butylthiophen-2-yl)-ethylene (18.5 g, 82%). Ethyl diazoacetate (13.0 g, 0.11 mol) in dry dichloromethane (150 ml) was added dropwise to a solution of (5-n-butylthiophen-2-yl)-ethylene (18.3 g, 0.11 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (50 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 1:1) to give ethyl 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylate (18 g, 71%).