Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:44]=[CH:43][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:45]3[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=3)[S:7][C:6]=2[CH:52]=1.[OH-].[K+]>C(O)C.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:44]=[CH:43][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40])([C:28]([OH:30])=[O:29])[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:45]3[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=3)[S:7][C:6]=2[CH:52]=1
Reactant: CCOC(=O)C(CCCCCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
Diethyl 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate (1.197 g, 1.59 mmol) was dissolved in ethanol (20 ml), and potassium hydroxide (3.58 g, 63.8 mmol) dissolved in water (10 ml) was then added. After stirring for 24 hours at 80° C., the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove ethanol, adjusted to pH 3 with 3N aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.1 g) as a brown product, which was then used for the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]=[N+:27]=[N-:28])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]12CC(CC1)=C[CH:32]=2>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:32]=[CH:31][N:28]=[N:27]4)[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C2CCC(=C1)C2
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
(5R)-3-(4-(1-Benzyl-1,2,5,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-5-azidomethyl-oxazolidin-2-one (4.55 g, 11.2 mM) and norbornadiene (5.15 g, 56 mM) were dissolved in dioxan (50 ml) and heated under reflux for 4 hours. The reaction mixture was evaporated and the product isolated by MPLC on silica, eluting with 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product as a gum which crystallised on trituration with diethyl ether (2.9 g).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:9][C:7]1([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][C@@H:3]([CH2:2][O:22][C:19]([CH3:20])=[O:21])[O:8]1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
In 10 mL of N,N-dimethylformamide were suspended 1.00 g (3.60 mmol) of tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate [synthesized by the process described in Example 6], 0.5 g (1.80 mmol) of tetra-n-butylammonium chloride and 0.89 g (10.8 mmol) of sodium acetate, and the suspension was stirred at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with 20 mL of water and extracted 3 times with n-hexane.
Reaction SMILES: [NH2:1][C:2]1([C:7]2[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=2[F:14])[CH2:4][CH:3]1[CH2:5][OH:6].ClCCl.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C([O-])(O)=O.[Na+].O.[Cl-].[Na+].O.C(OCC)(=O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:8]([F:14])=[C:7]([C:2]2([NH:1][C:20](=[O:21])[CH2:19][Cl:18])[CH2:4][CH:3]2[CH2:5][OH:6])[CH:12]=1
Reactant: NC1(c2cc(Br)ccc2F)CC1CO
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NC1(c2cc(Br)ccc2F)CC1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of [(1RS,2SR)-2-amino-2-(5-bromo-2-fluoro-phenyl)-cyclopropyl]-methanol (intermediate B8A) (387 mg, 1.49 mmol) in sat. aqueous NaHCO3-sol. (5 ml) and dichloromethane (DCM) (7 ml) at 0° C. was added chloroacetyl chloride (130 ul, 1.64 mmol) and the mixture was stirred at 0° C. for 30 min. Diluted with water, brine and ethyl acetate (EtOAc), separated phases, dried organic layer over sodium sulfate. Removal of the solvent in vacuum left the title compound as an off-white solid (497 mg, 99%), which was used without further purification. MS (ISP): m/z=336.1 [(M+H)+], 338.2 [(M+2+H)+] and 340.1 [(M+4+H)+].
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22]Cl.Cl>CN(C)C=O>[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCC=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCC=C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a mixture of 44 g of N-hydroxyphthalimide, 39 g of potassium carbonate, and 400 ml of N,N-dimethylformamide was added 41 g of 1,1,3-trichloro-1-propene at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into diluted hydrochloric acid to cause the deposition of crystals. These crystals were collected by filtration, washed with water and hexane in this order, and dried under reduced pressure, which afforded 66 g (yield, 90%) of N-(3,3-dichloro-2-propenyloxy)phthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Br:10][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[C:4]([Cl:8])[CH:5]=1
Reactant: BrBr
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mechanically stirred solution of 2,6-dichlorophenol (100 g) in acetonitrile (400 mL) was cooled to 0° C. and bromine (108 g) in acetonitrile (100 mL) was added dropwise. The red solution was stirred at 0° C. for an additional two hours and an saturated aqueous solution of sodium sulphite was added until the red color disappeared. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. Concentration of the combined organic phases gave 4-bromo-2,6-dichlorophenol as a yellow oil, which crystallized on standing. The crystalline material was washed with water and dried to give 126 g (85%) of colorless crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:5]2.[C:16]([OH:20])(=[O:19])[C:17]#[CH:18].C(N(CC)CC)C>C(#N)C.[Cu]I>[N:11]1([CH:7]2[C:8]3[C:4](=[CH:3][C:2]([C:18]#[C:17][C:16]([OH:20])=[O:19])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Ic1ccc2c(c1)CCC2N1CCCC1
Reactant: C#CC(=O)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)C#Cc1ccc2c(c1)CCC2N1CCCC1
Reaction time: 2 h

Procedure:
Under an argon atmosphere at 0° C., 0.5 g (1.59 mmol) of 1-(5-iodoindan-1-yl)pyrrolidine and 123 mL (2 mmol) of propynoic acid are dissolved in 25 mL of acetonitrile. 0.66 mL (4.79 mmol) of triethylamine, 30 mg (0.16 mmol) of copper (I) iodide, and 80 mg (0.11 mmol) of ditriphenylphosphine palladium dichloride are added to this solution and the mixture is stirred for 2 hours, while the solution is allowed to come up to ambient temperature. The purification is carried out by preparative HPLC (eluant: dichloromethane/methanol/ammonia (8:2:0.2)). Yield 0.1 g (24.5% of theory); C16H17NO2 (M=255.31); calc.: molecular ion peak (M+H)+: 256; found: molecular ion peak (M+H)+: 256.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:29][CH2:30][CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: Cn1cc(-c2cc3c(-c4cccc(NCC5CCNCC5)n4)n[nH]c3cn2)cn1
Yield: 55 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate were reacted and the product was deprotected to give 183 as a white solid (55% over two steps). 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 6.76-6.70 (m, 1H), 6.50 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 3.44-3.34 (m, 4H), 2.99 (d, J=12.2 Hz, 2H), 2.55-2.44 (m, 2H), 1.85-1.71 (m, 3H), 1.27-1.09 (m, 2H). LC/MS: m/z 389.2 [M+1]
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:7].[CH3:16][O:17][C:18](=[O:23])[C:19](OC)=[O:20]>C1C=CC=CC=1>[OH:20][C:19](=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:7])[C:18]([O:17][CH3:16])=[O:23]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(O)=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
To a well stirred suspension of freshly prepared sodium ethylate (820 mg, 12 mmol) in dry benzene (10 mL), 3,4-dichloroacetophenone (1.89 g, 10 mmol) and dimethyloxalate (1.18 g, 10 mmol) dissolved in dry benzene (20 mL), were added dropwise on cooling at +5° C., and under dry nitrogen atmosphere. The resulting dark red suspension was stirred at room temperature over 4 hours. The reaction mixture was then poured into ice/2N HCl (1:1 w/w), stirred for 5 minutes and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated in vacuo to afford a pale yellow solid, which was recrystallized from acetonitrile to yield the pure ester (2.4 g, 86%),colorless needles, mp. 122-123° C.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C([O-])([O-])=O.[Ca+2].[CH3:25][NH:26][N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>C(O)C>[CH3:25][N:26]([N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1)[C:5]1[N:6]=[CH:1][N:2]=[C:3]2[C:4]=1[N:8]=[CH:9][N:10]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: CNn1cccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)n1cccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To 100 ml absolute ethanol was added 6-chloropurine riboside (5.0 g, 0.017 mole), CaCO3 (3.5 g, 0.035 mole), and N-methyl-N-(1H-pyrrol-1-yl)amine (3.3 g, 0.035 mole). After stirring at 80° C. for three hours, the mixture was filtered, then evaporated to a solid which was eluted on a silica gel column with 5% methanol/dichloromethane via high pressure liquid chromatography to give a solid after evaporation, 4.0 g, m.p. 195°-197° C. This material was recrystallized from acetonitrile to give 2.4 g (41%) of N-methyl-N-(1H-pyrrol-1-yl)-9-β-D-ribofuranosyl-9H-purin-6-amine, m.p. 198°-199° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].[BH3-]C#N.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:35]3[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH:31]([CH3:30])[CH2:36]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol) and tert-butyl 2-methylpiperazine-1-carboxylate (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBH3CN (129 mg, 2.1 mmol) was added and the mixture was stirred for another 5 hours. Concentrated and the residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, yield 24%). LC-MS (ESI) m/z: 570 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH2:27][CH2:28][CH2:29][OH:30]>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][NH:27][CH2:28][CH2:29][OH:30])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: NCCO
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CNCCO)c(=O)n(CC3CC3)n2)cc1F
Yield: 72.1 %

Procedure:
Following the procedure of Example 9(4), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 2-aminoethanol were reacted to yield the title compound as a yellow oil (yield: 72.1%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[C:5](=[O:11])[C:4]2[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>CN(C)C=O>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]([NH:34][C:35]2[NH:39][N:38]=[N:37][N:36]=2)=[O:9])[C:5](=[O:11])[C:4]2[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:3]1=2
Reactant: Cn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2c3ccccc3oc(=O)c21
Yield: 94.6 %

Procedure:
Prepared by the method described for Ex. 17 from 1,5-dihydro-4-methyl-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (5.42 g, 0.02 mole), 1,1'-carbonyldiimidazole (6.48 g, 0.04 mole) and 5-aminotetrazole monohydrate (2.06 g, 0.02 mole) in dimethylformamide (90 ml). Recrystallization from dimethylformamide gives pale yellow crystals (6.4 g, 95%), m.p. above 300.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:12]1COCC1>>[CH3:1][C:2]1[O:6][C:5]2[CH2:7][CH2:8][C:9](=[CH2:12])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1cc2c(o1)CCCC2=O
Product: C=C1CCc2oc(C)cc2C1=O

Procedure:
To a solution of the furanone of Step A (164.5 g/1.10 mole) in about 400 ml THF was added, in four separate portions, N-methylanilium trifluoroacetate (TAMA) (243 g) and trioxymethylene (99 g) over 31/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and partitioned between Et2O and water, the layers separated and the aqueous layer was extracted twice with Et2O. The combined Et2O layers were washed exhaustively with water, with NaHCO3 and then with brine, dried over MgSO4 and conc. in vacuo to yield an amber oil. This oil was flash chromatographed on silica gel using CH2Cl2 as solvent in several runs of 10-20 g per run. Fractions containing the fast moving material were combined, concentrated in vacuo to obtain the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[C:20]([S:24]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[N:17]=1
Reactant: Cc1nc(-c2cccc(S(=O)(=O)Cl)c2)cs1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: Cc1nc(-c2cccc(S(=O)(=O)Nc3ccccc3S(N)(=O)=O)c2)cs1
Yield: 5 %

Procedure:
The title compound was synthesized as described for Example 178 in 5% yield, starting from 2-aminobenzenesulfonamide and 3-(2-methylthiazol-4-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: C(N(CC)[C@H]1C2C(=CC=CC=2)C[C@H]1O[C:14]([C@H:16]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:17]1)=[O:15])C.C(OC([C@H]1[C@H](C2C=CC(OC)=CC=2)O1)=O)(C)(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[SH:54].CC1C=CC=CC=1>C1(C)C(C)=CC=CC=1.CO>[OH:17][C@H:16]1[C:14](=[O:15])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[S:54][C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: Nc1ccccc1S
Reactant: CCN(CC)[C@H]1c2ccccc2C[C@H]1OC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
2.0 grams (4.8 mmol) of the mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (1S,2R)-1-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert-butyl ester (enantiomeric excess 80%) of Example V was dissolved in 20 ml of xylene+1 ml of methanol. This solution was heated to 120° C. and 600 mg (5.0 mmol) of 2-aminothiophenol was added drop by drop in 5 min. After 6 hours' heating at 120° C. the solution was cooled to 20° C. and 1.1 grams (6,0 mmol) of p-toluene sulphonic monohydrate was added. This was followed by 6 hours' heating at reflux temperature, during which 1-2 ml of a xylene/methanol mixture was removed through distillation. After cooling, the brown solution was dissolved in dichloromethane and washed with a 5% Na2CO3 solution in water and a 0.5M KH2PO4 solution in water. After drying with the aid of Na2SO4 and evaporation, the chemically pure product was obtained after chromatography using silica gel (eluant:toluene/ethyl acetate 2:1). 85% enantiomeric excess (determined with the aid of anisochrony in 1H NMR, see C. Giordano et al.; J. Org. Chem. 1991, (59), 2270). The enantiomeric excess was increased to >95% through one recrystallisation from toluene. White needles. Melting point: 200-202° C. [α]20D +109 (c=0.4, methanol). 1H NMR (200 MHz, CDCl3): 2.93 (d, 1H), 3.71 (s, 3H), 4.41 (dd, 1H), 5.02 (d, 1H), 6.74 (d, 2H), 7.03-7.21 (m, 2H), 7.29-7.44 (d+m, 3H), 7.61 (d, 1H) and 8.47 (br s, 1H). The (1S,2R)-1-(diethylamino)-2-indanol was recovered from the 0.5M KH2PO4 extraction solution.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.F[C:8](F)(F)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:20][C:21]#[N:22])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([C:15]2([CH2:20][C:21]([NH2:22])=[NH:1])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(CC(=N)N)CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred suspension of NH4Cl (1.3 g, 23.69 mmol) in dry toluene (30 mL) was added trimethylaluminium (2M solution in toluene) dropwise at 0° C., stirred at 0° C. for 15 min, then stirred at room temperature for 2 h. The solution of [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241) (2 g, 7.89 mmol) in toluene (10 mL) was added dropwise at the room temperature and the reaction mixture was heated at 80° C. for 16 h, the reaction mixture was cooled to 0° C., and the reaction mixture was poured into the slurry of silica gel (4 g) in CHCl3 (4 mL), stirred vigorously for 30 min at 0° C., the solid was filtered off through celite and washed with methanol (5×100 mL). The filtrate was concentrated and the crude product was taken up in 10% methanol in dichloromethane (200 mL) and stirred for 30 min. The solid was discarded by filtration and the filtrate was concentrated. The crude product was suspended in ether and a solid was collected by filtration and dried to get 2-(1-p-tolyl-cyclopentyl)-acetamidine (hydrochloride salt) (242) (1.4 g, 65.59%) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:10]=[CH:11][N:12]=[C:13]([O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:22])[CH:14]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: C[C@@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(O[C@@H]2CCCC[C@H]2C)ncn1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
In 1.6 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.4 ml of a tetrahydrofuran solution containing 0.06 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.4 ml of a tetrahydrofuran solution containing 0.18 g of 4-chloro-6-(trans-2-methylcyclohexyloxy)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 6-(2-butynyloxy)-4-(trans-2-methylcyclohexyloxy)pyrimidine (the present compound (175)).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[Cl:13][C:14]1[N:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[N:15]=[N:16][C:17]([CH2:20][Cl:1])=[CH:18][CH:19]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Cl)nn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Trichloroisocyanuric acid (3.62 g) was added to a solution of 3-chloro-6-methyl-pyridazine (5.00 g) in chloroform (130 mL) heated to 60° C. The mixture was stirred at 60° C. for 2 h and then at room temperature overnight. The mixture was filtered over Celite and the filtrate was concentrated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 98:2→70:30) to give the title compound as a colorless oil that solidified on standing. Yield: 2.48 g (39% of theory); Mass spectrum (ESI+): m/z=163/165/167 (2 Cl) [M+H]+.