Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([C:26]([N:1]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:27])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: C1COCCOCCOCCOCCN1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N1CCOCCOCCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
(+,−) Cis-2-Phenyl-cyclopentylamine (0.43 g, 2.7 mmol, from preparations 5 or 7) was dissolved in 15 mL of methylene chloride and cooled to 0° C. under nitrogen. 0.52 mL (3.5 mmol) of DBU was added followed by 0.39 mL (3.5 mmol) of isopropylsulfonyl chloride. Stirring was allowed to continue for 3 days while warming to room temperature. The reaction was washed with 1N HCl and the organic phase dried over sodium sulfate. Filtered, and concentrated in vacuo to a crude brown solid which was a 4:1 mixture of cis:trans by NMR. The isomers were purified by radial chromatography eluting with methylene chloride. 195 mg (27%) of the title compound (cis isomer) was isolated as a white solid as well as 15 mg of the more polar trans isomer. The NMR was consistent with the assigned structure.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[F:16][C:17]1[N:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[C:18]=1[F:26].[F-].[Cs+].ClCCl>CN(C=O)C.[Cl-].[Na+].O>[F:23][C:21]1[C:20]([F:24])=[C:19]([C:3]#[C:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[C:18]([F:26])=[C:17]([F:16])[N:22]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1C#Cc1c(F)c(F)nc(F)c1F
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of Trimethyl((2-nitrophenyl)ethynyl) silane, (11c) (1.10 g, 5.02 mmol) in DMF (10 mL) was added to the mixture of pentafluoropyridine (1.08 g, 6.53 mmol) and CsF(1.10 g, 7.52 mmol) in DMF (10 mL) slowly. The reaction mixture was stirred overnight. Brine (30 mL) and dichloromethane (60 mL) were added. Organic phase was separated and washed with water (30 mL×3). Solvent was evaporated by rotary evaporation and the residue was chromatographed (Hexane, then EtOAc:Hexane =1:30) to provide the desired product in 77% yield: 1H-NMR (300 MHz, CDCl3) δ 8.24 (dd, J=7.8, 1.5 Hz, 1H), 7.85 (dd, J=7.5, 1.5 Hz, 1H), 7.73 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.66 (ddd, J=7.8, 7.8, 1.5 Hz, 1H); 13C-NMR (150 MHz, CDCl3) δ 149.7, 143.7 (dm, J=234.1 Hz), 142.1 (dm, J=264.7 Hz), 135.5, 133.5, 131.2, 125.3, 116.7 (t, J=16.3 Hz), 116.2, 100.9 (t, J=3.2 Hz), 79.8 (t, J=4.1 Hz); HRMS (CI+): calcd for C13H5F4N2O2 [M+H]+ 297.02872, found 297.02911; m.p. 109-110° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[CH2:18]([O:17][C:15]([C:12]1[S:11][C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:14][CH:13]=1)=[O:16])[CH3:19]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#Cc2ccccc2)s1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
A solution of phenylacetylene (6.15 ml, 55.9 mmol), ethyl 2-bromothiazole-5-carboxylate (7.59 ml, 50.8 mmol), bis(triphenylphosphine)palladium(II) chloride (1.07 g, 1.52 mmol), copper (I) iodide (581 mg, 3.05 mmol), triethylamine (100 ml, 717 mmol) and tetrahydrofuran (225 mL) was stirred at 25° C. for 16 h. The reaction was worked up by concentrating to remove the THF and taken up in 400 mL of CHCl3. The CHCl3 was washed with 2×75 mL of 3.7% aq. HCl, 75 mL of brine, and dried (Na2SO4). The material was purified by silica gel chromatography using a gradient elution going from 4.5% to 8.5% EtOAc in hexanes over 30 minutes to give the titled compound, 2-phenylethynyl-thiazole-5-carboxylic acid ethyl ester (9.5 g, 73% yield), as a solid, which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:4].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:24][NH:25][CH3:26]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:25]([CH2:24][C:23]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=2)[CH3:26])[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CC(=O)CN1Cc1cccc(Cl)c1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)[C@@H]1C[C@H](N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cccc(Cl)c1
Yield: 95 %

Procedure:
As described for Example 64c, (S)-1-(3-chloro-benzyl)-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (7 mmol) was converted, using (3,5-bis-trifluoromethyl-benzyl)-methyl-amine instead of (2,4-difluorobenzyl)-methyl-amine, to the title product in 95% yield as yellow oil. MS m/e=509.9 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[CH2:6][CH:7]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[NH:12]C(=O)C)[N:8]=[C:2]12.[ClH:19]>CO.CC(O)C>[ClH:19].[ClH:19].[NH2:12][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:6][N:3]3[C:2]([S:1][CH2:5][CH2:4]3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1cccc(C2CN3CCSC3=N2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Nc1cccc(C2CN3CCSC3=N2)c1
Reaction time: 8 h

Procedure:
A solution of 1.00 g. (0.0038 mole) of 3'-(2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl)acetanilide (Example 8) in 17 ml. of 6N hydrochloric acid is heated at reflux for 2.5 hours and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aqueous sodium hydroxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g. of an oil, i.e., m-aminotetramisole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution and crystallization of the residue from 2-propanol gives 0.91 g. (81%) of cream colored solid, melting point 198°-201° C., dec.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(Cl)Cl.C(N(CC)CC)C.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>O>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=1)=[O:28])(=[O:9])[NH2:10]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccccc2C(N)=O)cc1
Yield: 88.2 %

Procedure:
To a well stirred mixture of anthranilamide (34.05 g; 0.25 mol), methylene chloride (650 ml) and triethylamine (~30 ml) is added p-toluoyl chloride (33 ml; 0.25 mol) dropwise over 25 minutes (a slight exotherm is noted). On completion of the addition, the reaction mixture is stirred for one hour, diluted with water (1000 ml). The mixture is stirred vigorously, filtered, the product washed with water and dried to afford 56.08 g solid, mp 206°-208° C.
Reaction SMILES: ClCCl.[CH3:4][O:5][CH:6]([CH3:9])[CH2:7][OH:8].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.O>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:8][CH2:7][CH:6]([O:5][CH3:4])[CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(C)COS(=O)(=O)c1ccc(C)cc1
Yield: 71.9 %

Procedure:
To dichloromethane (30 mL) mixture of 2-methoxypropan-1-ol (1.6 g, 17.8 mmol) and pyridine (20.0 mL), was added p-toluenesulfonyl chloride (4.07 g, 21.4 mmol) while stirring on ice, and the mixture was stirred at room temperature for five hours. To the mixture, were added water and ethyl acetate. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=2/1) to obtain the title compound (3.12 g, 12.8 mmol).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3cccc(F)c3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3cccc(F)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethne is added dropwise to a solution of 4.07 g of 4,5-bis(4-methoxyphenyl)-2-(3-fluorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 3.04 g of 4,5-bis(4-methoxyphenyl)-2-(3-fluorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22]>>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(O)CCCCCl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: C=CCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
This compound was obtained by reacting 7-Allyl-3-methylxanthine with 1-chloro-5-hydroxy-5-methylhexane in an analogous manner to Example 1.
Reaction SMILES: [C:1]([CH:4]1[S:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=O)[NH2:2].B>C1COCC1>[NH2:2][CH2:1][CH:4]1[S:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCSC(C(N)=O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCSC(CN)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.8 %

Procedure:
A solution of tert-butyl 2-carbamoylthiomorpholine-4-carboxylate (2.46 g, 10 mmol) in THF (80 mL) was cooled to 0° C. A solution of borane in THF (1.0 M, 40 mL, 40 mmol) was added over 15 minutes via addition funnel and the mixture was stirred at ambient temperature for 72 hours. The reaction was quenched by dropwise addition of methanol/acetic acid (18 mL, 9:1 v/v). The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and sat. aqueous Na2CO3. The aqueous layer was extracted with ethyl acetate and combined extracts were washed with water, brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded the crude desired material 2.11 g, which was used directly in the next step. MS (m/z): 233 (M+H)+
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
The compound (455 mg, 0.93 mmol) obtained in Example 4-3) was dissolved in methanol (4 mL). A 4 M solution (2.24 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (60 mL) and methanol (3 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (231 mg, 66%) in a white solid form.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([N+:22]([O-:24])=[O:23])=[CH:7][C:8]([CH3:21])=[C:9]([C:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2].CCCCCC.CCOC(C)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]([O:4][C:5]1[C:6]([N+:22]([O-:24])=[O:23])=[CH:7][C:8]([CH3:21])=[C:9]([C:11]2[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(=O)CC1

Procedure:
A solution of 8-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (0.1 mmol) in 2.5 mL of TFA and CH2Cl2 (1:4 v/v), is stirred at room temperature for 6 hours. After workup and silica flash chromatography (hexane/EtOAc 4:1), 4-(5-isopropoxy-2-methyl-4-nitrophenyl)cyclohex-3-enone is obtained. 1H NMR (CDCl3, 400 MHz) δ 7.63 (s, 1H), 6.81 (s, 1H), 5.73 (m, 1H), 4.62 (m, 1H), 3.07 (m, 2H), 2.68 (m, 4H), 2.27 (s, 3H), 1.37 (d. 6H). MS (ES+): 290.13 (M+1)+.
Reaction SMILES: C([O:4][CH:5](OC(C)C)[C:6]([CH3:26])([CH3:25])[C:7](=[O:24])[CH2:8][C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[O:24]=[C:7]([CH2:8][C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])[C:6]([CH3:26])([CH3:25])[CH:5]=[O:4]
Reactant: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C(OC(C)C)OC(C)C)OC(=O)OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C=O)OC(=O)OCC(Cl)(Cl)Cl

Procedure:
A mixture of (5R,6S)-1,1-diisopropoxy-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,6-trimethyl-8-nonen-3-one (4.3 g) and p-toluenesulfonic acid monohydrate (0.45 g) in 100 mL of 3:1 THF/water is heated at reflux for 7 hours. The mixture is cooled and poured into sat. aq. NaHCO3, then extracted with ethyl acetate. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Cl)nc4)cc3c2C1
Yield: 33.2 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 4.9 mg (0.101 mMol) 6-chloro-3-pyridinecarboxylic acid, 4.9 mg (31%) of the title compound were recovered as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].CS[C:16](=[NH:18])[NH2:17].[OH-].[Na+]>O>[NH2:17][C:16](=[N:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=1[F:1])[NH2:18]
Reactant: COc1ccc(C(=O)NN)c(F)c1
Reactant: CSC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)NN=C(N)N)c(F)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 42.4 %

Procedure:
To a solution of 4.26 g (23.15 mmol) of 2-fluoro-4-methoxybenzoic acid hydrazide in water (100 mL) are added 12.9 g (46.3 mmol) of S-methylpseudothiourea and 1.9 g (46.3 mmol) of sodium hydroxide pellets. The reaction is stirred at room temperature for 7 d. The reaction mixture is filtered and washed with water (50 mL). The solid is dried under reduced pressure at 40° C., then melted at 220° C. to give 2.22 g (9.82 mmol) of 2-fluoro-4-methoxybenzoic acid diaminomethylene hydrazide. Yield: 42%, ES-MS: m/z. The solid is melted at 220° C. to give 1.735 g (8.34 mmol) of 5-(2-fluoro-methoxyphenyl)-4H-[1,2,4]triazol-3-ylamine. Yield 36%, ES-MS: m/z 209 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:15][CH3:16]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CNC1
Reactant: CCI
Solvent: C1CCOC1
Product: CCN1CC(O)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
A mixture of 3-(3,4-difluorophenyl)azetidin-3-ol (0.3 g, 1.62 mmol) triethylamine (0.68 ml, 4.87 mmol) and iodoethane (0.19 ml, 2.44 mmol) in tetrahydrofuran (15 ml) was stirred at ambient temperature for 15 h. The solvent was evaporated and aqueous hydrochloric acid (50 mL. 10%) was added and the mixture was washed with tert-butyl methyl ether (2×50 ml). The aqueous phase was made basic by addition of aqueous sodium hydroxide (5 M) and extracted with tert-butyl methyl ether (2×50 ml). The combined organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the crude product (0.26 g). Purification by flash column chromatography on silica gel (ethyl acetate/methanol 1:1) gave 0.2 g (58%) of the title compound. The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether: M.p. 177-179° C. MS m/z (relative intensity, 70 eV) 213 (M+, 1), 141 (86), 127 (45), 114 (58), 58 (bp).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>C1COCC1.O>[Cl:11][C:9]1[C:10]2[C:2]([C:17]([OH:19])=[O:18])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=C=O
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (E-2) (6.24 g, 26.8 mmol, 1.0 eq) in anhydrous THF (100 mL) at 78° C. under argon, n-BuLi solution (2.5 M in THF, 23.6 mL, 59.0 mmol, 2.2 eq) is added dropwise (over 30 min). The reaction mixture is then stirred at −78° C. for 1 h and then dry ice (300 g) is added in portions under an argon atmosphere. The resulting mixture is allowed to warm to RT and then stirred at RT overnight. The reaction mixture is then diluted with H2O (200 mL) and extracted with ethyl acetate (50 mL×4). The aqueous layer is acidified with con. HCl to adjust the pH to 3-4. The precipitate is then collected by filtration, rinsed with H2O (30 mL) and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (G-1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:16](=[O:18])=[O:17]>CN(C)CCN(C)C.CCOCC>[C:11]([O:10][C:9]([NH:8][C:5]1[C:4]([C:16]([OH:18])=[O:17])=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Temperature: -15 °C

Procedure:
To 13 g of (6-chloro-pyridin-3-yl)-carbamic acid, tert-butyl ester in 24 mL of tetramethylethylenediamine and 300 mL of ether at −78° C. under an inert atmosphere was added slowly 68 mL of 2.5 M n-butyllithium/hexanes (3 eq). After the addition was complete, the reaction was allowed to warm to −15° C. for two hours then recooled to −78° C. Dry ice was allowed to sublime in a separate flask and the vapor was passed over the rapidly stirred reaction mixture while the cooling bath was removed and the reaction allowed to warm to 0° C. Sufficient water was added to dissolve the precipitated product and the resultant aqueous phase was washed twice with ether before acidifying with concentrated HCl. The precipitate was filtered, washed with water, and dried in vacuo to give 10.9 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, which was used as is for the next step: melting point 250° C. and higher (slowly decomposed); mass spectrum (negative mode, m/e): M−H 271.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:16])[C:3]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-:23].[Na+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:3]1[C:4]([CH3:16])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2)[C:2]=1[I:23])[CH3:22]
Reactant: [I-]
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1I
Temperature: 80 °C

Procedure:
Ethyl 7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5 g, 15.35 mmol) and sodium iodide (9.20 g, 61.4 mmol) were suspended in acetonitrile (80 mL) and the resulting mixture was heated at 80° C. for 2 h. At this point LCMS indicated completion of the reaction and appearance of the desired product. After cooling to rt, the reaction mixture was diluted with ethyl acetate and washed with water and aqueous Na2S2O3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was triturated with ethyl acetate/hexane to afford ethyl 6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.7 g, 13.7 mmol, 89% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 4.51 (d, J=7.0 Hz, 2H), 4.25 (d, J=7.0 Hz, 2H), 4.02 (s, 2H), 2.68 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H). LCMS (M+H)=418.2.